Epithelial Cysts Research Articles

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.

Papel de la ecografía con contraste en la evaluación de lesiones focales esplénicas

The purpose of this article is to evaluate the role of contrast-enhanced ultrasound in the characterization of non-traumatic focal splenic lesions.Focal splenic lesions are less common than in other abdominal organs like the liver. Conventional ultrasound and Doppler ultrasound have a limited role in the characterization of splenic lesions, resulting in many of them unspecified.Contrast ultrasound is an accessible, cheap, and safe technique which can help in the immediate characterization of lesions incidentally detected in the ultrasound examination, being a good alternative to others imaging techniques.We review in detail the technique and the main indications. We also analyze imaging findings and enhancement pattern by using representative case of the main splenic lesions for both benign (epithelial cyst, cystic lymphangioma, hemangioma, hamartoma, infarction, sclerosing angiomatous nodular transformation, abscesses, sarcoidosis), and malignant (lymphoma, metastasis) and its pathological correlation in some cases.

Ex vivo detection of lipopolysaccharide immunopositivity in Rushton bodies.

Our aim was to investigate how bacterial lipopolysaccharide (LPS) is immunoexpressed in periapical lesions. By surprise we detected Rushton bodies (RBs) whose origin has been debatable to be positive for LPS. Samples of radicular cysts (N=70) were stained in order to identify variations in LPS immunoexpression indicating bacterial background. For immunostaining, we used an anti-LPS antibody from Escherichia coli, and for visualization Horse Radish Peroxidase labeled polymer as the secondary antibody. RBs showed positivity for LPS in radicular cysts. After collection of radicular cyst samples (70 in total), we noted that all RBs (N=25) histologically detected in tissue samples were positive for LPS. Furthermore, calcification in the cyst capsule showed immunopositivity. We demonstrate for the first time that LPS is present in RBs, indicating that host response to bacteria might be the initial cause of the formation of these hyaline bodies in the cyst epithelium and cyst capsule calcifications.

CFTR and PC2, partners in the primary cilia in autosomal dominant polycystic kidney disease.

Defects in the primary cilium are associated with autosomal dominant polycystic kidney disease (ADPKD). We used a combination of animal models, Western blotting, and confocal microscopy and discovered that CFTR and polycystin 2 (PC2) are both colocalized to the cilium in normal kidneys, with the levels of both being decreased in cystic epithelia. Cilia were longer in CFTR-null mice and in cystic cells in our ADPKD animal models. We examined septin 2, known to play a role in cilia length, to act as a diffusion barrier and to serve as an enhancer of proliferation. We found that septin 2 protein levels were upregulated and colocalized strongly with CFTR in cystic cells. Application of VX-809, the CFTR corrector, restored CFTR and PC2 toward normal in the cilia, decreased the protein levels of septin 2, and drastically reduced septin 2 colocalization with CFTR. Our data suggest that CFTR is present in the cilia and plays a role there, perhaps through its conductance of Cl-. We also postulate that septin 2 is important for localizing CFTR to the apical membrane in cystic epithelia.NEW & NOTEWORTHY CFTR is present in the primary cilia together with polycystin 2 (PC2). Ablation of CFTR makes cilia longer suggesting that CFTR plays a role there, perhaps through its conductance of Cl.

Significance of morphological studies in the diagnostics of bilial intraepithelial neoplasia in nonparasitic liver cysts

Biliary intraepithelial neoplasia (BilIN) according to modern data is considered as an obligate precancer of the bile ducts. As BILIN progresses, cholangiocarcinoma often develops, characterized by a low five-year survival rate. The aim of this work is to describe the morphological characteristics of BilIN in the epithelium of nonparasitic liver cysts. The material is described after primary and repeated (15) surgical interventions in 99 patients. The morphological manifestations of intraepithelial neoplasia in non-parasitic dysontogenetic liver cysts were studied, their role in the development of liver cholangiocarcinoma was established.

The Importance of Effective Ligand Concentration to Direct Epithelial Cell Polarity in Dynamic Hydrogels.

Epithelial cysts and organoids are multicellular hollow structures formed by correctly polarized epithelial cells. Important in steering these cysts from single cells is the dynamic regulation of extracellular matrix presented ligands, and matrix dynamics. Here, control over the effective ligand concentration is introduced, decoupled from bulk and local mechanical properties, in synthetic dynamic supramolecular hydrogels formed through noncovalent crosslinking of supramolecular fibers. Control over the effective ligand concentration is realized by 1) keeping the ligand concentration constant, but changing the concentration of nonfunctionalized molecules or by 2) varying the ligand concentration, while keeping the concentration of non-functionalized molecules constant. Theresults show that in 2D, the effective ligand concentration within thesupramolecular fibers rather than gel stiffness (from 0.1 to 8kPa) regulates epithelial polarity. In 3D, increasing the effective ligand concentration from 0.5 × 10-3 to 2 × 10-3 m strengthens the effect of increased gel stiffness from 0.1 to 2kPa, to synergistically yield more correctly polarized cysts. Through integrin manipulation, it isshown that epithelial polarity is regulated by tension-based homeostasis between cells and matrix. Theresults reveal the effective ligand concentration as influential factor in regulating epithelial polarity and provide insights on engineering of synthetic biomaterials for cell and organoid culture.

Epithelial Inclusion Cyst of the Foot Causing Pressure Ulcer and Skin Breach

Epithelial inclusion cysts are benign lesions that rarely occur in the extremities in the absence of trauma. They may demonstrate slow but progressive enlargement. This case relates to a 50 year old female who presented with a grade 1 pressure ulcer to the plantar surface of her right foot, associated with discomfort mobilising and pain upon wearing traditional footwear. Surgical excision was performed, and histology demonstrated an epithelial inclusion cyst, leading to complete recovery and resolution of the plantar pressure ulcer.

A novel in vitro model to study prolonged Pseudomonas aeruginosa infection in the cystic fibrosis bronchial epithelium.

Pseudomonas aeruginosa (PA) is known to chronically infect airways of people with cystic fibrosis (CF) by early adulthood. PA infections can lead to increased airway inflammation and lung tissue damage, ultimately contributing to decreased lung function and quality of life. Existing models of PA infection in vitro commonly utilize 1-6-hour time courses. However, these relatively early time points may not encompass downstream airway cell signaling in response to the chronic PA infections observed in people with cystic fibrosis. To fill this gap in knowledge, the aim of this study was to establish an in vitro model that allows for PA infection of CF bronchial epithelial cells, cultured at the air liquid interface, for 24 hours. Our model shows with an inoculum of 2 x 102 CFUs of PA for 24 hours pro-inflammatory markers such as interleukin 6 and interleukin 8 are upregulated with little decrease in CF bronchial epithelial cell survival or monolayer confluency. Additionally, immunoblotting for phosphorylated phospholipase C gamma, a well-known downstream protein of fibroblast growth factor receptor signaling, showed significantly elevated levels after 24 hours with PA infection that were not seen at earlier timepoints. Finally, inhibition of phospholipase C shows significant downregulation of interleukin 8. Our data suggest that this newly developed in vitro "prolonged PA infection model" recapitulates the elevated inflammatory markers observed in CF, without compromising cell survival. This extended period of PA growth on CF bronchial epithelial cells will have impact on further studies of cell signaling and microbiological studies that were not possible in previous models using shorter PA exposures.

P036 A comparative study of cell culture inserts for in vitro modeling of the cystic fibrosis airway epithelium

P036 A comparative study of cell culture inserts for in vitro modeling of the cystic fibrosis airway epithelium

A rare case of pedunculated vulval angiomyofibroblastoma

A rare benign mesenchymal tumour that predominantly occurs in lower genital tract, more frequently vulvo vaginal areas of young to middle-aged women, rarely occurs in retroperitoneum. It needs to be differentiated from other benign conditions like Gartner’s duct cyst, epithelial inclusion cyst, fibroepithelial polyps. It grows more slowly and is non tender, non invasive, and have least tendency for local recurrence. The histologic findings of the tumors are abundant thin-walled blood vessels with hypocellular and hypercellular areas. Almost all tumor cells have immunoreactivity for both desmin and vimentin. It also has estrogen and/or progesterone receptors, but staining for cytokeratin is negative. Here is a case of AMFB of the vulva occurring in a 62-year-old woman, involving the left labia majora. The patient described that her vulva mass grew over few years. The dimension of the tumor was measured as 18*12*4 cms. Excision biopsy done and sent for histopathology.

Epithelial polarization in the 3D matrix requires MST3 signaling to regulate ZO-1 position.

Apical-basal cell polarity must be tightly controlled for epithelial cyst and tubule formation, and these are important functional units in various epithelial organs. Polarization is achieved through the coordination of several molecules that divide cells into an apical domain and a basolateral domain, which are separated from tight and adherens junctions. Cdc42 regulates cytoskeletal organization and the tight junction protein ZO-1 at the apical margin of epithelial cell junctions. MST kinases control organ size through the regulation of cell proliferation and cell polarity. For example, MST1 relays the Rap1 signal to induce cell polarity and adhesion of lymphocytes. Our previous study showed that MST3 was involved in E-cadherin regulation and migration in MCF7 cells. In vivo, MST3 knockout mice exhibited higher ENaC expression at the apical site of renal tubules, resulting in hypertension. However, it was not clear whether MST3 was involved in cell polarity. Here, control MDCK cells, HA-MST3 and HA-MST3 kinase-dead (HA-MST3-KD) overexpressing MDCK cells were cultured in collagen or Matrigel. We found that the cysts of HA-MST3 cells were fewer and smaller than those of control MDCK cells; ZO-1 was delayed to the apical site of cysts and in cell-cell contact in the Ca2+ switch assay. However, HA-MST3-KD cells exhibited multilumen cysts. Intensive F-actin stress fibers were observed in HA-MST3 cells with higher Cdc42 activity; in contrast, HA-MST3-KD cells had lower Cdc42 activity and weaker F-actin staining. In this study, we identified a new MST3 function in the establishment of cell polarity through Cdc42 regulation.

A giant congenital ranula: ignorance leading to feeding difficulties

The term “Ranula” originates from the Latin Word Rana which means “underbelly of a frog.” Ranula are epithelial retention cyst or mucus extravasation pseudo cyst arising from the sublingual glands. They are rare in children. A one-year-old female was brought to paediatric surgery emergency OPD by her mother with complaints of swelling arising from oral cavity since birth, gradually increased in size to attain current size. Mother also gives History of difficulty in feeding. Clinical examination revealed a large protruded tongue, with a cystic swelling in the floor of the mouth measuring around 6×4 cm, with elevation of the tongue. Child was further evaluated; ultrasound was suggestive of ranula. Marsupialisation of the cyst was done. Intraoperatively, cyst fluid was aspirated for analysis and cyst wall was opened and excised, lateral margins of cyst were sutured to base of mouth. Cyst fluid analysis revealed elevated amylase and normal LDH levels. The post-operative period was uneventful. The histopathology report showed a pattern consistent with ranula. Child was followed up for a period of 1 year and there was no evidence of recurrence. We report a case of giant congenital ranula. The rarity of this condition in children and its atypical size make this case report unique. We treated the child with marsupialization and there was no recurrence noted. Hereby I would like to state that congenital symptomatic ranulas though rare can be managed with marsupialisation.

Adrenal cysts: an emerging condition.

Adrenal cysts are rare lesions representing approximately 1-2% of adrenal incidentalomas. The majority of these rare lesions are benign. Rarely, phaeochromocytomas and adrenal malignant masses can present as cystic lesions and can occasionally be difficult to distinguish from benign cysts. Histologically, adrenal cysts are subdivided into pseudocysts, endothelial cysts, epithelial cysts and parasitic cysts. The radiological appearance of an adrenal cyst is generally similar to that of cysts in the kidney. They are thus well demarcated, usually rounded, with a thin wall and homogenous internal structure, low attenuating (<20 Hounsfield Units) on CT, low signalling on T1-weighted MRI sequences and high signalling on T2-weighted MRI sequences, and anechoic or hypoechoic on ultrasonography. Benign adrenal cysts have a slight female predominance and are usually diagnosed between the ages of 40 and 60. Most adrenal cysts are asymptomatic and are detected incidentally, although very large adrenal cysts can lead to mass effect symptoms, with surgery required to alleviate the symptoms. Thus, conservative management is usually recommended for asymptomatic cysts. However, when uncertainty exists regarding the benign nature of the cyst, additional work-up or follow-up is needed. The management of an adrenal cyst should preferably be discussed at an adrenal multidisciplinary team meeting.

Unusual application of topical brimonidine for the management of epithelial cysts

The mainstay management of progressive epithelial cysts spans from fine-needle aspiration of the cyst content to radical en bloc excision. Such a surgical approach may result in cyst rupture, recurrence, or collateral tissue damage. Based on previous experience, we aimed at evaluating the off-label use of topical brimonidine as a conservative measure for treating epithelial cysts of the iris and conjunctiva before commencing a surgical excision. We describe two different cases of epithelial cysts in which topical brimonidine was issued with successful outcome, making the more traditional surgical intervention redundant.

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1RC/RC mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1RC/RC and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1RC/RC mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCDcl4 cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCDcl4 epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology.

Mast Cell Tryptase and Carboxypeptidase A3 in the Formation of Ovarian Endometrioid Cysts.

The mechanisms of ovarian endometrioid cyst formation, or cystic ovarian endometriosis, still remain to be elucidated. To address this issue, we analyzed the involvement of mast cell (MC) tryptase and carboxypeptidase A3 (CPA3) in the development of endometriomas. It was found that the formation of endometrioid cysts was accompanied by an increased MC population in the ovarian medulla, as well as by an MC appearance in the cortical substance. The formation of MC subpopulations was associated with endometrioma wall structures. An active, targeted secretion of tryptase and CPA3 to the epithelium of endometrioid cysts, immunocompetent cells, and the cells of the cytogenic ovarian stroma was detected. The identification of specific proteases in the cell nuclei of the ovarian local tissue microenvironment suggests new mechanisms for the regulatory effects of MCs. The cytoplasmic outgrowths of MCs propagate in the structures of the stroma over a considerable distance; they offer new potentials for MC effects on the structures of the ovarian-specific tissue microenvironment under pathological conditions. Our findings indicate the potential roles of MC tryptase and CPA3 in the development of ovarian endometriomas and infer new perspectives on their uses as pharmacological targets in personalized medicine.

Uncommon congenital swellings around external ear in adults

Congenital cyst around external ear appearing in adulthood is rare condition. Such lesions arising around the external auditory canal that requires surgical excision are uncommon and their clinical and surgical management is often difficult because these anomalies have variable relationship with facial nerve. In this study, we investigated characteristics of congenital cysts of the external ear by analyzing their clinical and histo-pathological features. Here we described 3 unique cases with localization of an epithelial cyst, type 1 branchial cleft cyst and epidermal inclusion cyst in adults which are uncommon, congenital and rare.

Multidirectional corneoconjunctival transposition in the treatment of large keratomalacia in 7 dogs and 5 cats.

To describe the use of multidirectional corneoconjunctival transposition (CCT) as a surgical treatment for large keratomalacia. A prospective study including dogs and cats initially presenting with keratomalacia larger than 6 × 6 mm and affecting more than half of the corneal thickness. Signalment, concurrent eye diseases, ulcer size, bacterial culture and susceptibility testing results, follow-up, and outcome were recorded. The surgery consisted of harvesting of two or three opposite corneoconjunctival grafts, after removal of the malacic tissue using a square-edge keratectomy. The medical treatment consisted of administration of topical and systemic antibiotics, topical atropine, and N-acetylcysteine. Follow-up examinations were performed at D7, D14, D21, and D28, and then at various time points. The corneal clarity score (CCS) was recorded upon completion of the follow-up period. Seven dogs and five cats were included. Brachycephalic dogs were overrepresented, with no breed predisposition in cats. Concurrent eye diseases were corneal pigmentation in three dogs, hypopyon in two dogs, nictitating membrane wound in one dog, and corneal perforation in one cat. The size of the keratomalacia ranged from 6 × 6 to 9.5 × 11.5 mm. The short-term complications were suture dehiscence (two of 12) and progression of the keratomalacia (one of 12). The long-term complications were corneal pigmentation (10 of 12), corneal epithelial inclusion cyst (two of 12), and marginal synechiae (one of 12). All animals were sighted at the last follow-up. The median CCS was G3 (range G2-G4). Multidirectional CCT is an effective surgical treatment for large keratomalacia in dogs and cats.

Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.

Squamous Cell Carcinoma Arising From Odontogenic Cyst Epithelium or Oral Mucosa Epithelium After Marsupialization of Odontogenic Radicular Cyst in Posterior Mandible?

Squamous cell carcinomas (SCCs) are common malignant tumors in the oral and maxillofacial region. However, SCCs secondary to marsupialization of odontogenic radicular cysts are extremely rare. The authors report an unusual case of a 43-year-old male presented with dull pain in the right molar region of the mandible without numbness of lower lips, who had a long history of smoking, alcohol consumption, and betel nut chewing. Computerized tomography revealed a round well-defined unilocular radiolucent at the apex of lower right premolars, 2 nonvital teeth. The clinical diagnosis was the radicular cyst of the right mandible. The patient was initially treated with root canal therapy of the teeth followed by marsupialization with a mandibular vestibular groove incision. While the patient did not follow the instruction of irrigation of the cyst and had no regular follow-up. The reexamination of computerized tomography indicated a round well-defined unilocular radiolucent at the apex of lower right premolars and filled with a soft tissue without clear boundary with buccal muscles at 31 months follow-up. There were no masses or ulcer around the mandibular vestibular groove incision and the patient had no sign of numbness of lower lips. The clinical diagnosis was the radicular cyst of right mandible with infection. A curettage was performed. However, the pathologic diagnosis was well-differentiated SCC. An extended radical surgical resection including segmental resection of the right mandible was performed. The histopathology was well-differentiated SCC without the cyst epithelium and invasion of bone, which can be distinguished from primary intraosseous SCC. The case indicates that marsupialization performed in patients with a history of smoking, alcohol consumption, and betel nut chewing, has a risk of suffering from oral SCC.