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PubMed2000

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes.

Squamous differentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous differentiation further, we examined the effect of altering E2F activity in primary human keratinocytes induced to differentiate. Promoter activity for the proliferation-associated genes, cdc2 and keratin 14, are inhibited during squamous differentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of differentiation markers (transglutaminase type 1 and keratin 10) in differentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce differentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-specific marker genes and suppresses squamous differentiation-specific marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas. Oncogene (2000).

Base Sequence↗

PubMed2006

Short communication: expression of human endogenous retrovirus-R gene links to differentiation of squamous cells.

To investigate the biological roles of human endogenous retrovirus-R (HERV-R) in vivo, we established transgenic rats carrying the full sequence of the viral genome with control of its own long terminal repeat promoter. The Env protein was expressed on the surface of the epidermis of fetal HERV-R transgenic rats on day 10 of gestation. The epidermal Env expression disappeared by day 18 of gestation. After day 18 of gestation, the Env protein was detected in the prickle layer of the esophageal epithelium of transgenic rats. Interestingly, it was not detected in the basal layer of the epithelium, and the expression in the granular layer was weaker than in the prickle layer. These findings suggest that expression of HERV-R is linked not only to the development but also to the differentiation of squamous cells. Next, we examined alterations in the expression of the HERV-R env gene in cultured human squamous cells after exposure to all-trans retinoic acids (ATRA). The env expression was increased by ATRA in a dose-dependent manner, while the expression of transglutaminase 1 (TGM1), a terminal marker for squamous differentiation, was decreased. TGM1 is expressed in the granular layer of the squamous epithelium, and ATRA suppresses the differentiation of cultured squamous cells. Thus, these in vitro data also suggest that HERV-R expression is regulated by a mechanism closely related to the differentiation of squamous cells. This study is the first to demonstrate the association of HERV-R expression and differentiation of squamous cells.

Animals↗

PubMed1992

Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases.

In this study of 40 cases of basaloid squamous cell carcinoma, 83% arose in the pyriform sinus, base of tongue, tonsil, and larynx. The 35 men and five women ranged in age from 27 to 88 years (median 62). In patients for whom social habits were recorded, 24 of 26 patients were smokers and 22 of 25 drank ethanol. Most presented with stage III or IV disease. Twenty-seven patients had regional metastases at the time of presentation and 15 developed distant metastases. Seventeen patients died with disease (median survival 18 months). The tumors were composed of moderately pleomorphic basaloid cells forming nests, cords, and frequent cribriform patterns. Squamous dysplasia of surface mucosa, focal squamous differentiation within invasive basaloid squamous cell carcinoma, or foci of conventional squamous cell carcinoma were present, alone or in combination. All studied neoplasms were immunohistochemically positive for keratins with the 34 beta E12 antibody. Approximately 80% were immunoreactive using AE1/AE3 or CAM 5.2. Epithelial membrane antigen, carcinoembryonic antigen, and S100 protein were found in 83%, 53%, and 39%, respectively, of the cases. Diffuse, weak immunoreactivity for neuron-specific enolase was seen in 75% of tumors. Synaptophysin, chromogranin, muscle-specific actin, and glial fibrillary acidic protein were absent. Basaloid squamous cell carcinoma has been confused with adenoid cystic carcinoma and small cell undifferentiated carcinoma, but is usually distinguishable in routine hematoxylin and eosin-stained sections, or, in rare problematic cases, with the aid of immunohistochemical studies. Distinction is warranted because the biologic behavior of basaloid squamous cell carcinoma differs from that of both of these lesions.

Adult↗

PubMed1990

Papillary serous carcinoma of the ovary with squamous differentiation.

Two cases of serous carcinoma of the ovary with squamous differentiation are described. These neoplasms occurred in two women who were 63 and 46 years old and who presented with International Federation of Gynecology and Obstetrics (FIGO) stage IIB and III disease, respectively. The first tumor recurred following chemotherapy; radiotherapy was given, but the patient died of tumor at 4 years. The second neoplasm did not respond to chemotherapy and caused the patient's death at 2 years. In the first case, the squamous differentiation occurred as compact nests of ovoid to spindle cells intermixed with a papillary serous carcinoma component. The squamous component of the second case developed as single or small groups of enlarged, eosinophilic cells, often multinucleated, within nests of papillary serous carcinoma with typical psammoma bodies. In the latter case, intercellular bridges were identified by light microscopy. Both cases showed squamous features by immunohistochemistry, staining positively for 57-kd keratin, although in the first case but not the second there was also some weaker staining for 54-kd keratin, probably indicating incomplete squamous differentiation with retained glandular features. Electron microscopy in both cases revealed prominent cytoplasmic tonofilaments in the squamous component. These two cases reinforce the concept that squamous differentiation, although more frequent in some other types of common epithelial tumors, may occur in serous ovarian carcinomas as well.

Carcinoma, Papillary↗

PubMed1983

Induction of squamous metaplasia: requirement for cell multiplication, and competition with lobuloalveolar development in cultured mammary glands.

Mouse mammary glands were previously shown to undergo either of two courses of development and differentiation in whole organ culture. The combination of insulin, prolactin, aldosterone, and hydrocortisone induces a structural development of lobuloalveoli, followed by casein production. In the second course, the mixture of dibutyryl cyclic AMP, prostaglandins E1, E2 and B1, and papaverine brings about an extensive squamous metaplasia and excessive keratinization. In the present study, the foci of the metaplastic squamous cells appeared to originate from single or very few cells. A preferential stimulation of squamous cell multiplication was involved in the induction process. Twice the relative number of nuclei incorporated 3H-thymidine in the squamous metaplastic cells than in the surrounding cuboidal epithelium, according to autoradiography. The necessity for cell multiplication was indicated by the reversible and complete inhibitions of both the metaplastic squamous development and 3H-thymidine incorporation by 1 mM hydroxyurea in the culture medium. Simultaneous inductions of both courses of development and differentiation revealed a competitive and reciprocal relationship between the two pathways. The concurrent expressions of both courses were considerably less than those achieved when either pathway was induced alone. Only the combination of the three types of inducers of squamous metaplasia was able to compete effectively with the hormonal induction of lobuloalveolar development and differentiation. The findings suggest that individual metaplastic squamous foci may originate as clones of cells by processes that require cell multiplication, rather than through a direct non- replicative conversion of pre-existent cells of the cuboidal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation.

OBJECTIVE: Barrett's esophagus is associated with significantly increased risk of development of esophageal adenocarcinoma. Replacing columnar epithelium with the normal squamous lining in this condition offers the possibility of decreasing the risk of degeneration to invasive adenocarcinoma. This study aimed to establish the feasibility of argon beam plasma coagulation (ABPC), in conjunction with control of gastroesophageal reflux, to restore the squamous lining. METHODS: Thirty patients with Barrett's esophagus (four low-grade dysplasia, three high-grade) were recruited from our surveillance program, and underwent endoscopic ABPC. RESULTS: Twenty-seven patients completed treatment, with macroscopic replacement of their columnar lining by squamous epithelium, histologically confirmed in all 27, and followed up for a median of 9 months (range, 6-18 months). Two patterns of squamous replacement were identified: 70% of patients showed squamous epithelium with no persistent intestinal metaplasia, and in 30% the new squamous epithelium covered areas of underlying intestinal metaplasia. One patient has withdrawn from the study. Two esophageal perforations, with one death, occurred early in the study. CONCLUSION: ABPC, in conjunction with control of gastroesophageal reflux, allows squamous regrowth in both benign and dysplastic Barrett's esophagus. Despite the theoretical safety advantages of ABPC over techniques such as laser, esophageal perforation may occur with this technique. It is too soon to recommend ABPC for dysplastic or nondysplastic Barrett's because follow-up is too short to show a decreased incidence of and mortality from adenocarcinoma.

Adenocarcinoma↗

PubMed2005

Differences in ERK activation in squamous mucosa in patients who have gastroesophageal reflux disease with and without Barrett's esophagus.

OBJECTIVES: In some patients with gastroesophageal reflux disease (GERD), the reflux-damaged esophageal squamous epithelium heals through the process of intestinal metaplasia (resulting in Barrett's esophagus) rather than through the regeneration of more squamous cells. We hypothesized that squamous epithelium in Barrett's esophagus might have abnormalities in activation of the extracellular-regulated kinases 1 and 2 (ERK1/2) signaling pathway that may facilitate esophageal repair through metaplasia in response to acid-induced injury. METHODS: Endoscopic biopsies were taken from distal esophageal squamous mucosa in patients who had GERD with and without Barrett's esophagus and in controls, before and after esophageal perfusion with 0.1 N HCl acid. Basal ERK1/2 phosphorylation, acid-induced ERK1/2 activity and phosphorylation, and localization of phosphorylated ERK1/2 were determined using immunoblotting, Western blotting, and immunohistochemistry. RESULTS: Compared to patients with Barrett's esophagus, patients with GERD exhibited significantly lower baseline levels of phosphorylated ERK1/2 expression (35 +/- 4%vs 90 +/- 21% control, p= 0.01) Acid exposure significantly increased ERK1/2 activity (346.6 +/- 51.90 to 446.8 +/- 62.44 RIU, p= 0.02) and phosphorylation (3.55 +/- 1.26 to 4.49 +/- 1.25 [ratio phospho/total ERK], p= 0.01) in the squamous mucosa of GERD patients, but not in those with Barrett's esophagus or in controls. CONCLUSIONS: Between patients with Barrett's esophagus and patients with uncomplicated GERD, there are significant differences in baseline levels and in acid-induced activation of ERK1/2 in esophageal squamous epithelium. To our knowledge, this is the first description of a molecular, phenotypic feature that distinguishes the esophageal squamous mucosa of GERD patients with and without Barrett's esophagus.

Adult↗

PubMed1987

Molecular cloning of gene sequences regulated during squamous differentiation of tracheal epithelial cells and controlled by retinoic acid.

A cDNA library was constructed from polyadenylated RNA present in squamous differentiated rabbit tracheal epithelial cells. Screening of the cDNA library was aimed at identifying RNAs that were abundant in squamous cells and expressed at low levels in undifferentiated cells. Two different recombinants were obtained containing inserts, 0.86 and 0.77 kilobases (kb) in size, that hybridized to mRNAs 1.0 and 1.25 kb in length. These RNAs were present at approximately 50-fold higher levels in squamous cells than in proliferative or confluent retinoic acid-treated cells. The increase in the levels of the 1.0- and 1.25-kb RNAs correlated closely with the onset of squamous differentiation and was not related to induction of terminal cell division. Treatment of rabbit tracheal epithelial cells with transforming growth factor beta, which induces squamous differentiation in these cells, also resulted in elevated levels of the 1.0- and 1.25-kb RNAs. The increased levels of these RNAs in squamous cells appeared to a large extent to be regulated at a posttranscriptional level. Retinoic acid not only inhibited the increase in the levels of the 1.0- and 1.25-kb RNAs but also reversed the expression of these RNAs in squamous cells. These results suggest that retinoic acid affects, directly or indirectly, molecular events that induce alterations in the posttranscriptional processing of the transcripts corresponding to the 1.0- and 1.25-kb RNAs.

Animals↗

PubMed1983

Interaction of asbestos with metaplastic squamous epithelium developing in organ cultures of hamster trachea.

The normal mucociliary epithelium of the respiratory tract in chronic cigarette smokers often is replaced focally by a metaplastic squamous epithelium. Because asbestos workers who smoke have a substantially greater risk of bronchogenic carcinoma than nonsmokers, we hypothesized that interaction of asbestos with squamous epithelium might be a contributing factor. To address this question, an in vitro model was developed to study the interaction of asbestos with both mucociliary and squamous epithelium. Explants of tracheas from hamsters were cultured in either a chemically defined minimal essential medium, which maintains a differentiated epithelium, or a nutritionally complex medium, which encourages the development of squamous metaplasia. Scanning electron microscopy (SEM) was used to measure quantitatively the development of a squamous epithelial surface on the explants. The interaction of chrysotile and crocidolite asbestos with cells of the mucociliary and squamous epithelium was studied using both SEM and transmission electron microscopy (TEM). Long fibers of asbestos were cleared, whereas shorter fibers were phagocytized by cells of the mucociliary epithelium. In contrast, asbestos was phagocytized by superficial squamous cells regardless of fiber length, and fibers penetrated between intercellular junctions in the metaplastic epithelium. The relevance of these interactions to the induction of bronchogenic carcinoma is discussed.

Animals↗

PubMed2001

Histological characteristics of induced acute peptic injury in equine gastric squamous epithelium.

The objective of the study reported here was to characterise the microscopic appearance of peptic-injured equine gastric squamous epithelium in relation to the duration of peptic injury. Erosions and ulcers were induced in equine gastric squamous epithelium using a feed deprivation protocol that results in prolonged increased gastric acidity. Specimens of normal gastric mucosa and mucosa with lesions created after 48 and 96 h of feed deprivation were compared for characteristics associated with angiogenesis and mucosal proliferation. Fifteen mature horses, 9 geldings and 6 mares, age 3-20 years, were divided into 3 groups. Group 1 (n = 5) had normal-appearing gastric squamous mucosal epithelium and had been killed due to problems unrelated to the gastrointestinal tract. Groups 2 (n = 5) and 3 (n = 5) had lesions induced in the gastric squamous epithelium by alternating 24 h periods of feed deprivation and ad libitum access to hay, for totals of 48 and 96 h feed deprivation, respectively. Following lethal injection of barbiturate, stomachs were removed and fixed by filling with 4-6 l 10% buffered formalin. Sections were made from lesions in the gastric squamous epithelium adjacent to the margo plicatus along the right side of the stomach/greater curvature and the lesser curvature. Measurements of total epithelial thickness, keratinised epithelium, nonkeratinised epithelium, epithelial projections, capillary extension into the epithelium and lamina propria thickness were made. The cross-sectional areas of arterial and venous vascular structures in the lamina propria at the lesions and their margins were measured using image analysis software. All horses, except one, in Group 2 developed erosions or ulcers in the gastric squamous epithelium after feed deprivation. There were several changes in the epithelium adjacent to erosions and ulcers, compared to normal epithelium, from horses in Groups 2 and 3: total epithelial thickness was significantly (P<0.05) greater, including both keratinised and nonkeratinised layers in most specimens; the length of epithelial projections and extent to which capillaries from the lamina propria extended toward the luminal surface, and the cross-sectional area of vascular structures (arterioles, capillaries, venules) in the lamina propria were significantly greater. Epithelial thickness of erosion beds was not significantly less than normal epithelium, although a greater proportion of the epithelium in erosions consisted of epithelial projections (Group 1, 23%; Group 2, 76%; Group 3, 72%). The cross-sectional area of vascular structures in the lamina propria beneath erosions was significantly greater than in normal mucosa only in Group 2 tissues, whereas in the lamina propria of ulcers it was significantly greater than in normal mucosa only in Group 3 tissues. The epithelial proliferation and increased vascular cross-sectional area in the lamina propria associated with peptic-induced gastric lesions are consistent with processes associated with the initiation of ulcer healing, and these changes temporally coincided with the initiation of peptic insult to the gastric squamous epithelium. These findings demonstrate that processes that promote ulcer healing begin soon after peptic injury and that they progress even with repeated peptic injury. Furthermore, our findings support observations that gastric ulcers often heal without medical intervention, and the theory that medications that reduce gastric acidity do not initiate healing, but rather facilitate ulcer healing by providing a microenvironment that is optimal for healing to proceed.

Animals↗

PubMed2003

Imiquimod for the treatment of Bowen's disease and invasive squamous cell carcinoma.

Topical imiquimod is an immune response modifier FDA approved for the treatment of anogenital warts. Recent studies have reported its effectiveness in the treatment of some types of basal cell carcinomas. There have also been some case reports and case series reporting success treating of squamous cell carcinoma in situ with imiquimod. We report two patients with squamous cell carcinoma in situ and one with invasive squamous cell carcinoma treated with 5% imiquimod cream. Lesions were located on shin, posterior shoulder, and nasal tip. 5% imiquimod cream was applied at night for six weeks. Side effects included erythema and crusting in one patient. Biopsies taken four weeks after treatment revealed no residual squamous cell carcinoma in situ or squamous cell carcinoma. Topical 5% imiquimod cream is becoming established as a promising treatment for squamous cell carcinoma in situ. It also seems to be an alternative treatment for some cases of squamous cell carcinoma.

Administration, Cutaneous↗

PubMed2006

[Human embryonic esophagus squamous epithelial cells cultured through microscopic stripping technique and digestion in vitro].

OBJECTIVE: To discuss the application possibility of the microscopic stripping technique used in the primary culture of human embryonic esophagus squamous epithelial cells, and of the methods for the isolation, depuration and subculture of the esophagus epithelial cells in vitro. METHODS: The squamous epithelial cells were obtained from the esophagus mucous membrane of the 20-week abortion fetus through the microscopic stripping technique, and were digested with trypsin. Then, the morphological, immunohistochemical observation and the growth curve of the isolated cells were studied. RESULTS: The isolated cells were spherical in the cell suspension and spherical-like or polygon-like after attachment to the culture flask. The squamous epithelial specialized cytokeratin staining was strongly positive. And the morphological studies by the transmission electron microscopy indicated that the cultured cells were squamous epithelial cells. The squamous epithelial cells reached the peak level 3-4 days after the transfer of the culture. The absorbance at 3 and 4 days was significantly higher than that at 1, 2, 5 and 6 days (P < 0.05). CONCLUSION: A large number of squamous epithelial cells can be available with the microscopic stripping technique and the digestion method. The cultured squamous epithelial cells can be proliferated quickly, and fit for the tissue engineering study.

Cell Culture Techniques↗

PubMed1986

Extensive squamous metaplasia in gynecomastia.

Extensive squamous metaplasia is described in a case of gynecomastia. Numerous ducts in all sections of breast tissue revealed multiple foci of squamous metaplasia, many of which included large, papillary excrescences of keratinizing squamous cells into duct lumens, with foci of dyskeratosis. Review of four years of gynecomastia cases from our surgical pathology files revealed a total incidence of squamous metaplasia equaling six of 40 cases of gynecomastia, including the case reported here. The other five cases included only one or two small foci of squamous metaplasia. These findings demonstrate that squamous metaplasia in gynecomastia is not rare, but is usually very limited. However, an unusual case, such as that reported here, may show extensive, florid squamous metaplasia, without associated inflammation or neoplasm.

Adult↗

PubMed1987

Retinoic acid and substratum regulate the differentiation of rabbit tracheal epithelial cells into squamous and secretory phenotype. Morphological and biochemical characterization.

In this paper we show that the expression of the squamous differentiated phenotype and mucosecretory phenotype by cultured rabbit tracheal epithelial cells can be regulated by substratum and the presence of retinoic acid. Cells grown on a type I collagen gel matrix in the absence of retinoic acid stratify and undergo squamous differentiation as indicated by the appearance of squamous, cornified cells. Under these conditions cells are rich in desmosomes and heavy tonofilament bundles. These cells also express several biochemical markers for squamous differentiation such as high levels of type I transglutaminase and cholesterol sulfate. High levels of transglutaminase were also observed in areas of squamous metaplasia in tracheas of vitamin A-deficient hamsters. Treatment with retinoic acid not only blocked squamous differentiation as evidenced by the inhibition of the biochemical markers for squamous differentiation but induced the appearance of columnar, polarized cells many of which contained secretory granules. These granules stained positively with periodic acid thiocarbohydrazide and certain lectins indicating the presence of glycoconjugates. Analysis of radiolabeled glycoconjugates released into the medium indicated the synthesis of mucous glycoproteins. It appears that retinoic acid determines the pathway of differentiation whereas the collagen gel matrix is permissive for the expression of both phenotypes. The morphological and biochemical similarities between this in vitro cell system and the normal and metaplastic tracheal epithelium suggest that this rabbit tracheal epithelial cell system is a useful and relevant model to study the regulation of differentiation of the tracheobronchial epithelium.

Animals↗

PubMed1985

Salivary gland components involved in the formation of squamous metaplasia.

Squamous metaplasia is not an uncommon feature of a number of salivary gland lesions. Arterial ligation of rat submandibular and sublingual salivary glands was used for study of the processes and cell types involved in the development of the squamous metaplasia that occurs in ischemic and infarcted portions of gland parenchyma 6 to 8 days following vessel ligation. Light and electron micrographs show that the principal portion of salivary gland tissue undergoing squamous metaplasia is the acinar-intercalated duct cell complex. Early stages of this process involve a gradual dedifferentiation of acinar cells and hyperplasia of acinar, duct luminal cells, and myoepithelium. Subsequently, both luminal and myoepithelial cells have increasing accumulation of tonofilaments and formation of desmosomes, and centrally located cells may undergo keratinization. Immunohistochemical staining of ischemic salivary gland tissue with developing squamous metaplasia was performed with the use of rabbit antisera to human epidermal and Mallory body cytokeratins. The two antisera gave complementary patterns in normal acini and ducts, with antibody to epidermal cytokeratin (ECK) staining only myoepithelial cells and antibody to Mallory body cytokeratin (MBCK) staining mainly luminal epithelial cells. In early phases of squamous metaplasia (6 days after ligation), antibody to ECK stained central and peripheral (myoepithelial) cells, but by 8 days after ligation only central cells were stained. At 6 days after ligation, a proportion of central cells in squamoid clusters stained with antibody to MBCK, and myoepithelial cells were unstained. By 8 days after arterial ligation, cell clusters exhibiting squamous metaplasia were completely unstained with antibody to MBCK, despite the presence ultrastructurally of numerous tonofilament bundles in both types of cells forming these clusters. The propensity for squamous alteration of acinar-intercalated duct complexes has important connotations for salivary gland tumors such as pleomorphic adenoma and mucoepidermoid carcinoma.

Animals↗

PubMed1996

Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells.

Human bronchial epithelial (HBE) cells undergo squamous differentiation in response to a variety of conditions in tissue culture, and retinoid treatment has been shown to reverse this process. Retinoids mediate their effects through the retinoic acid and retinoid X nuclear receptors (RAR and RXR, respectively), which form RAR-RXR heterodimers, RXR homodimers, and heterodimers of RXR and certain orphan receptors. These receptor dimers bind to distinct response elements, activating separate pathways. In this study, we investigated the roles of RAR and RXR signaling pathways in the inhibition of HBE squamous differentiation. After induction of squamous differentiation by confluent growth, HBE cells were treated with retinoids that selectively activate RARs (E-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaienyl)-1- propenyl] benzoic acid), RXRs (4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid), or both RARs and RXRs (9-c/s retinoic acid). These retinoids inhibited the mRNA expression of the squamous differentiation markers transglutaminase type I, involucrin, keratin 5, and keratin 13, suggesting that inhibition of HBE squamous differentiation could be mediated by activation of either RAR or RXR signaling pathways. We examined the role of AP-1 as a potential effector of these retinoid pathways. AP-1 transcriptional activity was reduced markedly by these retinoids, and a concomitant, but proportionally smaller, reduction in AP-1 DNA binding was observed. Furthermore, treatment of squamous HBE cells with the retinoid SR11238, which inhibited AP-1 without activating retinoid receptor transcriptional properties, reduced the expression of transglutaminase type I and involucrin. These findings support the hypothesis that, in HBE cells, RAR and RXR signaling pathways inhibit AP-1 transcriptional activity, and this contributes to retinoid-induced reversal of HBE squamous differentiation.

Alitretinoin↗

PubMed1995

Epstein-Barr virus in the proliferative diseases of squamous epithelium in the oral cavity.

The presence of Epstein-Barr virus was analyzed in 79 cases of oral epithelial proliferative diseases by polymerase chain reaction, in situ hybridization for Epstein-Barr virus-deoxyribonucleic acid and Epstein-Barr virus-encoded small messenger ribonucleic acid and immunohistochemistry for Epstein-Barr virus latent membrane protein. These lesions were histologically categorized as invasive squamous cell carcinoma (n = 36), carcinoma in situ (n = 10), verrucous carcinoma (n = 4), leukoplakia (n = 19), and papilloma (n = 10). Epstein-Barr virus genomes were detected in 19 squamous cell carcinoma (52.8%), four carcinoma in situ (40%), and one leukoplakia (5.3%); none of the verrucous carcinoma or papilloma cases were positive with polymerase chain reaction. By deoxyribonucleic acid in situ hybridization, positive signals were observed in the nuclei of cancer cells in 10 cases, in infiltrating lymphocytes in three, and both in one case. In patients with carcinoma in situ, only a single case was positive. In one case of leukoplakia positive signals were found in upper and middle layer squamous cells. The results by Epstein-Barr virus-encoded small messenger ribonucleic acid in situ hybridization revealed the same distribution as that by deoxyribonucleic acid in situ hybridization. Latent membrane protein was expressed only in the epithelial cells of leukoplakia but not in cases with squamous cell carcinoma and carcinoma in situ. These findings suggest that Epstein-Barr virus infection of oral squamous epithelium may be carcinogenic; alternatively, the virus may merely exist in epithelial cells of squamous cell carcinoma, carcinoma in situ, and leukoplakia as a passenger.

Adult↗

PubMed2026

2026 International Society for the Study of Vulvovaginal Disease terminology for vulvar intraepithelial neoplasia and squamous intraepithelial lesions.

The 2026 International Society for the Study of Vulvovaginal Disease terminology for vulvar intraepithelial neoplasia and squamous intraepithelial lesion requires p16 and p53 immunohistochemistry for classification into human papillomavirus-associated or human papillomavirus-independent disease. p16 and p53 are tumor suppressor proteins; block positive p16 staining is a surrogate marker for genomic integration of oncogenic human papillomavirus, while null or overexpressed p53 staining correlates with TP53 mutation. Human papillomavirus-associated and human papillomavirus-independent vulvar intraepithelial neoplasia represent 2 distinct entities with different diagnostic considerations, treatments, surveillance strategies, and prognoses. The designation of 'neoplasia' vs 'lesion' reflects biological behavior, with neoplasia signifying an established risk of progression to cancer. Human papillomavirus-associated disease maintains a 2-tier nomenclature: human papillomavirus-associated vulvar intraepithelial neoplasia for precursors to vulvar squamous cell carcinoma vs low-grade squamous intraepithelial lesion and condyloma for transient human papillomavirus manifestations. While human papillomavirus-associated vulvar intraepithelial neoplasia is preferred, high-grade squamous intraepithelial lesion is retained as acceptable in some settings to maintain consistency with nomenclature for analogous lesions across the lower genital tract. Human papillomavirus-independent disease almost always arises from longstanding lichen sclerosus. The updated terminology for human papillomavirus-independent precursors to squamous cell carcinoma is human papillomavirus-independent vulvar intraepithelial neoplasia, subcategorized as p53 mutant or p53 wild type. Verrucous vulvar intraepithelial neoplasia is a subtype of p53 wild type human papillomavirus-independent vulvar intraepithelial neoplasia and the usual precursor to verrucous carcinoma. Vulvar aberrant maturation encompasses human papillomavirus-independent lesions of uncertain neoplastic potential arising in lichen sclerosus that raise concern for but are not diagnostic of human papillomavirus-independent vulvar intraepithelial neoplasia. Collaboration between clinicians and pathologists is essential to achieve accurate diagnosis, optimal individualized treatment, and consistent application of this terminology in practice and research.

Humans↗