Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe.

Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.

Histologic and genomic characterization of a primary mucinous carcinoma of the skin.

Aims: Primary skin mucinous carcinoma is a rare sweat gland neoplasm with a high local recurrence rate after conventional excision but a low distant-metastasis rate. The genetic underpinning of skin mucinous carcinoma is presently unknown. Here, we sought to define whether the repertoire of somatic mutations of a primary mucinous carcinoma of the skin would be similar to that of mucinous breast carcinomas, given the histologic similarities between these tumor types. Methods and results: The tumor was situated in the dermis and partially involved the subcutaneous fat. Tumor cells were suspended in periodic acid-Schiff diastaseresistant- positive mucin lakes and expressed cytokeratin 7, synaptophysin and estrogen receptor. DNA samples extracted from microdissected tumor and matched normal tissue were subjected to massively parallel sequencing targeting 410 cancer-related genes. The skin mucinous tumor was found to have a low tumor mutation burden, but to harbor a clonal GATA3 frameshift mutation (p. T418Hfs*89) and amplification of FOXA1, genes not uncommonly altered in breast mucinous carcinomas. Conclusions: In this primary skin mucinous carcinoma, GATA3 and FOXA1 driver genetic events were identified, consistent with a possible developmental relationship between skin and breast mucinous neoplasms.

Analysis of RANK-c interaction partners identifies TRAF3 as a critical regulator of breast cancer aggressiveness.

Breast cancer is a highly heterogeneous disease both at the histological and molecular levels. We have previously shown that RANK-c is a regulator of NF-κB signaling and exerts a suppressive effect on aggressive properties of ER negative breast cancer cells, while there is an opposite effect on ER positive cell lines. In order to identify molecular determinants that govern the opposing function of RANK-c in breast cancer cells we employed the two cell lines with the highest degree of phenotypic divergence upon RANK-c-expression (SKBR3 and BT474) and identified proteins that interact with RANK-c by affinity-enrichment mass spectrometry (AE-MS) analysis. Annotating enriched proteins with NF-κB signaling pathway revealed TRAF3 as an interacting partner of RANK-c in SKBR3 cell protein lysates, but not in BT474 breast cancer cells in which RANK-c induces cell aggressiveness. To determine the role of TRAF3 in the phenotype of BT474-RANK-c cells, we reconstructed the TRAF3/RANK-c interaction both in parental BT474 and RANK-c expressing cells and tested for aggressive properties through colony formation, migration and invasion assays. TRAF3 forced expression was able to reverse BT474 phenotypic changes imposed by RANK-c, rendering cells less aggressive. Finally, TRAF3 gene expression data and TRAF3 immunohistochemical (IHC) analysis on breast cancer samples indicated that TRAF3 expression correlates with Overall Survival (OS), Recurrence Free Survival (RFS) and several clinicopathological parameters (histological grade, proliferation index) of breast cancer disease.

ILK expression in human basal cell carcinoma correlates with epithelial-mesenchymal transition markers and tumour invasion.

AIMS: Epithelial-mesenchymal transition (EMT) has been known to play a significant role in tumour progression. Integrin-linked kinase (ILK) has been recently added to the growing list of EMT regulators that control some aspect of carcinogenesis. The aim was to study ILK expression and its relevance to EMT markers in human basal cell carcinoma (BCC). METHODS AND RESULTS: Paraffin-embedded tissue sections from 100 human BCC cases were processed by immunohistochemistry for the expression of ILK, E-cadherin, Snail, beta-catenin and alpha-smooth muscle actin (alpha-SMA). ILK overexpression was observed in 100% of cases and strongly correlated with tumour invasion and infiltrative BCC. Loss of membranous E-cadherin was found in 71% of cases while nuclear immunoreactivity for E-cadherin was also observed in 90% of the tumours. Snail, nuclear beta-catenin and alpha-SMA expression was detected in 100%, 99% and 97% of tumours, respectively. Aberrant expression of E-cadherin, nuclear beta-catenin and alpha-SMA correlated with BCC tumour invasion. Interestingly, there was a significant correlation between ILK expression and all the EMT markers examined. CONCLUSIONS: ILK overexpression in BCC is implicated in tumour progression probably through the induction of an EMT-related molecular profile. Nuclear localization of E-cadherin in BCC is also associated with aggressive tumour features.

Immunologic adverse reaction associated with low-carbide metal-on-metal bearings in total hip arthroplasty.

BACKGROUND: An increased incidence of periprosthetic osteolysis, resulting in loss of biologic fixation, has been reported in contemporary THAs with low-carbide metal-on-metal compared with metal-on-polyethylene couple bearings. Although a hypersensitivity reaction attributable to Co and Cr debris is reportedly a potential cause for failure of THAs with high-carbide bearings, there are no evidence-based data for this reaction in low-carbide metal-on-metal bearings, although such hypersensitivity might be related to osteolysis. QUESTIONS/PURPOSES: We investigated whether there were differences in immunologic hypersensitivity reactions in retrievals from revised THAs with ceramic-on-polyethylene versus metal-on-metal bearing couples. PATIENTS AND METHODS: We compared newly formed capsule and periprosthetic interface membranes from revision surgery for aseptic failure from 20 patients with low-carbide bearings and 13 patients with ceramic-on-polyethylene bearings. For control tissue, we obtained samples from the hip capsule during the primary THA implantation in 13 patients with low-carbide bearings and seven with ceramic-on-polyethylene bearings. We examined the tissues with conventional histologic and immunohistochemical methods. RESULTS: Compared with tissue from the control subjects and patients with ceramic-on-polyethylene bearings, the tissues from patients with low-carbide metal-on-metal bearings were associated with (1) extensive necrosis and fibrin exudation in the newly formed hip capsule and (2) diffuse and perivascular lymphocytic infiltration of a higher degree than in the hips with ceramic-on-polyethylene bearings in conventional histologic examination, and (3) more T than B cells. CONCLUSIONS: The conventional histologic and immunohistochemical findings in tissues retrieved from failed THAs with low-carbide metal-on-metal bearings are consistent with a link between hypersensitivity and osteolysis with low-carbide bearing couples.

Estrogen receptor-beta expression in human laryngeal carcinoma: correlation with the expression of epithelial-mesenchymal transition specific biomarkers.

Laryngeal carcinoma is a malignancy of the respiratory tract with a significantly higher male to female ratio, suggesting involvement of gender-depended factors in the pathogenesis. Estrogen influences the pathological processes of hormone-dependent cancers, such as breast, prostate and ovarian cancers, through its receptors, estrogen receptor-alpha (ER-alpha) and -beta (ER-beta). While ER-alpha promotes cell proliferation, recent studies indicate that ER-beta is protective against carcinoma progression into an invasive state. However, it is unclear whether ER-beta plays a role in laryngeal cancer. In the present study we examined the expression of ER-beta in 80 invasive human squamous laryngeal carcinomas by immunohistochemistry and correlated ER-beta expression with markers of epithelial-mesenchymal transition (EMT). ER-beta was expressed in 83% of tumour specimens where it was localized in the nuclei of tumour cells. The expression of ER-beta correlated positively with the maintenance of E-cadherin and beta-catenin at cell junctions and negatively with the loss of E-cadherin, nuclear translocation of beta-catenin and increased TNM stage. We concluded that estrogen receptor-beta expression is documented in laryngeal cancer indicating a possible role in the pathogenesis of this malignancy. It is suggested that ER-beta could protect tumour cells from acquiring aggressive EMT features such as E-cadherin downregulation and nuclear beta-catenin activation.

Investigating differentiation mechanisms of the constituent cells of sex cord-stromal tumours of the ovary.

SOX-9, an essential factor for male sexual development, can be induced by prostaglandin D2 in a Sry-independent mechanism. Recent data suggest that the hedgehog pathway is involved in the differentiation of normal Sertoli and Leydig cells. The purpose of our study was to investigate the mechanisms involved in the differentiation of ovarian sex cord-stromal tumour (SCST) cells. Two Sertoli-Leydig cell tumours and two granulosa cell tumours with a minor Sertoli element were studied using immunohistochemistry on paraffin-embedded tissue sections. Sertoli cells expressed anti-Mullerian hormone (AMH), SOX-9, prostaglandin D synthase (Pgds) and bcl-2 (in four of four cases); sonic hedgehog (Shh) and p53 (in three of four cases) and androgen receptors (AR; in one of four cases). Ki-67 index ranged from 10% to 50%. Leydig cells expressed Shh and AR (two of two cases), while they showed no expression of p53, bcl-2 and 0% Ki-67 index. Granulosa cells expressed AMH, Pgds, Shh, estrogen receptors, progesterone receptors, AR and bcl-2 (in two of two cases) and p53 (in one of two cases). Ki-67 index was 10% and 40%, respectively. Further investigation is required to clarify the role of the molecules outlined above in the histogenesis of ovarian SCST, as Pgds-mediated SOX-9 upregulation could provide a reasonable explanation for the presence of testicular differentiation in ovarian SCST.

Study of the eye and lacrimal glands in experimental iron overload in rats in vivo.

A variety of syndromes leading to hemosiderosis in men cause ocular lesions. The purpose of the present study was to determine the distribution of iron and of transferrin in the eyes and lacrimal glands of rats in experimental hemosiderosis, so as to achieve a better understanding of the formation of the ocular lesions observed in patients with advanced hemosiderosis. In order to achieve hemosiderosis the rats were fed 3% (w/w) carbonyl iron or received i.p. or i.v. polymaltose iron. Hemosiderin deposits were detected in macrophages lying in the interlobular connective tissue of lacrimal glands, in the interstitial connective tissue of the choroid, in the ciliary body, in the iris and extracellularly in the sclera in all animals that received iron i.v. Also, scanty hemosiderin laden macrophages were found to a lesser degree in interstitial connective tissue of the choroid and in the interlobular connective tissue of lacrimal glands in animals that received iron i.p. No iron deposits were detected in the eye and lacrimal glands of control rats and in rats that were on an iron enriched diet. No transferrin was detected in the eye and in the lacrimal glands, neither in the control rats nor in the rats that received iron. Experimental iron overload leads to increased iron deposition in tissues of the eye and lacrimal glands, whereas no transferrin could be detected in the aforementioned organs.

Ultrasonography in differentiation between chronic viral hepatitis and compensated early stage cirrhosis.

AIM: To assess the value of gray scale (GS) and colour Doppler ultrasonography (CDU) in differentiating the progression of chronic viral hepatitis (CVH) and compensated liver cirrhosis (CIR). METHODS: Seventy-two patients and 32 normal individuals who were used as controls were studied. Forty-four patients suffered from CVH and 28 from CIR. All patients were underwent to liver biopsy. Multiple qualitative and quantitative variables were studied in liver, portal vein (PV), hepatic artery (HA) and spleen with GS and CDU. On the basis of the obtained CDU data, several known indexes were calculated. In addition, alternative indices [PV diameter (D)/time average mean velocity (VTAM), HA/PV VTAM ratio] were calculated and studied. RESULTS: ROC analysis showed that PV congestion index, PV D/VTAM and HA/PV VTAM indices had the best sensitivity and specificity in discriminating CVH from CIR. Stepwise discriminant analysis showed that 88.9% of the originally grouped cases could be correctly classified by the three qualitative and four quantitative variables selected as statistically significant predictors. Among the CVH patients who underwent to biopsy, statistically significant changes were found in those at fibrosis stage 5 compared to fibrosis stages 1-4. CONCLUSION: Simple GS and CDU parameters discriminate CVH from CIR. The alternative Doppler indexes can accurately differentiate chronic virus hepatitis from cirrhosis. These indexes can be used in monitoring chronic virus hepatitis and avoiding unnecessary biopsies.

RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

Case report: laparoscopic adrenalectomy in a patient with primary adrenal malignant melanoma.

We report a case of laparoscopic management of a primary malignant melanoma of the left adrenal gland. A 42-year-old male presented a 55 x 60-mm round, inhomogeneous, noninvasive mass of the left adrenal gland. Hormone-activity values were within normal range. The mass was removed laparoscopically en bloc along with the left adrenal gland, and its histopathologic evaluation was consistent with the features of a malignant melanocytic tumor. Postoperatively, the patient presented no signs of fever or remarkable blood loss and was discharged on the third day in good clinical condition. He is free of disease 1 year later.

Primary small cell bladder carcinoma: a case report and review of the current literature.

Primary small cell bladder carcinoma is an extremely rare and highly aggressive tumor. Unfortunately, the optimal therapeutic strategy for the tumor is still unknown. Recently, a two-stage system for limited and extensive small cell bladder carcinoma has been suggested in analogy to the practiced staging and treatment of small cell lung carcinoma. We present a new case of small cell bladder carcinoma and discuss relevant current literature.

Does coralline hydroxyapatite conduct fusion in instrumented posterior spine fusion?

OBJECTIVES: This study was conducted to investigate the course of incorporation of coralline hydroxyapatite in human spine. SUMMARY OF BACKGROUND DATA: Conventional techniques for surgical treatment of spine have a substantial failure rate and associated morbidity. Bone graft substitutes are an alternative technique to enhance fusion rates and limit the morbidity associated with spine fusion using autologous iliac crest bone graft. There are some experimental studies supporting the use of hydroxyapatite in spine surgery. MATERIAL & METHODS: During revision surgery specimens derived from the fusion mass from 15 operations in 13 patients, who received spinal instrumentation and fusion in cervical, thoracic, and lumbar spine and addition of coralline hydroxyapatite. The age of patients at the time of revision surgery was 46 +/- 20 years. The time lapsed from the implantation of coralline hydroxyapatite and revision surgery was 11 +/- 9 months. The indication for revision surgery was infection, pseudarthrosis, technical error, and pain related to bulky hardware. The diagnosis for the primary fusion was degenerative disease, trauma and scoliosis, and the material of instrumentation used was composed from titanium alloy. The coralline hydroxyapatite was applied on the decorticated posterior elements of the instrumented spine. Material from ten different places from the fusion mass was intraoperatively taken in all patients and was sent for histological evaluation using the Hematoxylin-eosin histological stain technique and photomicroscope. RESULTS: Under photomicroscope there was a remarkable concentration of foreign-body like giant cells & development of inflammatory granulation tissue around hydroxyapatite, which was gradually replaced by dense connective collagen tissue. Both inflammatory granulation and collagen tissue showed areas with foreign body reaction. In the cases, where bone has developed, the most initial finding was the presence of osteoblasts & apposition of osteoid in contact to hydroxyapatite granules. In a later phase, cancellous and lamellar bone has developed as a result of secondary ossification. Bone formation was observed in 11/15 cases and was related with the patient's age in favor of young patients (R=0.56, P<0.05), while there was no correlation with time lapsed from operation. CONCLUSION: Coralline hydroxyapatite conducts bone formation in spine surgery because in the vast majority of the operated cases for different spinal disorders bone and osteoid has developed around the implanted coralline hydroxyapatite.

Current therapeutic leads for the treatment of melanoma: targeted immunotherapy in the post-genomic era.

Metastatic melanoma has a poor prognosis and until today most therapeutic approaches are ineffective. Advances in molecular pathology and genome analysis technologies have led to the identification of genetic events and immune regulatory checkpoints that provide novel targets for pharmaceutical intervention in melanoma. Development of selective mitogen-activated kinase (MAPK) pathway inhibitors was the first major achievement coming from genetic studies that identified a constitutively active MAP kinase pathway and BRAF activating mutations in melanoma. At the same time, the manipulation of immune system checkpoints through monoclonal antibodies changed clinical practice and led to further improvement of patient outcomes. In an effort to further develop melanoma targeted therapies that depend on the genetic profile of a given patient, high-throughput genome wide approaches (next-generation sequencing [NGS], gene arrays, etc) have been employed for the characterization of genetic alterations in the patient's tumor. In the near future, the combined information from the genetic and immune background of an individual will provide the basis for a personalized, highly targeted approach in the treatment of melanoma.

Decreased ezrin and paxillin expression in human urothelial bladder tumors correlate with tumor progression.

OBJECTIVES: F-actin binding proteins ezrin and paxillin are involved in cell adhesion and cell migration/invasion. The aim of the study was to investigate their role in urothelial bladder carcinogenesis. MATERIALS AND METHODS: Expression of ezrin and paxillin was studied by immunohistochemistry in 104 and 96 cases of urothelial bladder tumors, respectively. Correlations with clinicopathologic data and expression of p53, E-cadherin, and ß-catenin were examined. RESULTS: Positive ezrin and paxillin protein expression was found in 99% and 93.7% of cases, respectively. Membranous expression of ezrin was significantly lower in high grade tumors and correlated with invasion. Multivariate analysis showed that ezrin is an independent predictor of muscularis propria invasion. Paxillin expression was significantly decreased in urothelial carcinomas compared with tumors of low malignant potential and low paxillin levels also correlated with advancing tumor stage and invasion. A statistically significant correlation was found between membranous ezrin and E-cadherin as well as between ezrin and paxillin expression in urothelial tumors. CONCLUSIONS: Down-regulation of ezrin and paxillin in urothelial bladder tumors is associated with aggressive tumor features and invasiveness.

Myxoglobulosis of the appendix: a case associated with ruptured diverticulum.

We describe a case of the extremely rare entity of myxoglobulosis of the appendix from a 45-year-old white man who was operated urgently with the clinical diagnosis of acute appendicitis. Sectioning of the appendix revealed the presence in the dilated appendiceal lumen of numerous whitish opaque globules ranging in size from 0.2 to 0.7 cm in diameter. A ruptured diverticulum and several smaller ones were also found. On microscopic examination, the globules consisted of faintly eosinophilic laminations of mucin surrounding an amorphous granular core. The mucin was identified by positivity with histochemical mucin stains. After thorough microscopic examination of the appendix, our case was diagnosed as myxoglobulosis due to mucosal hyperplasia, associated with ruptured diverticulum and acellular extra-appendiceal mucin deposits.

Loss of inhibitor of growth (ING-4) is implicated in the pathogenesis and progression of human astrocytomas.

Inhibitor of growth 4 (ING-4) is a tumor suppressor gene that interacts with nuclear factor-kappaB (NF-kappaB) and represses its transcriptional activity. Several lines of evidence suggest that the tumor suppressor gene ING-4, the transcription factor NF-kappaB and its target genes matrix metalloproteases MMP-2, MMP-9 and urokinase plasminogen activator (u-PA) are critically involved in tumor invasion. The aim of the present study was to investigate immunohistochemically the expression pattern of ING-4, NF-kappaB and the NF-kappaB downstream targets MMP-2, MMP-9 and u-PA in human astrocytomas from 101 patients. We found that ING-4 expression was significantly decreased in astrocytomas, and ING-4 loss was associated with tumor grade progression. Expression of p65, a NF-kappaB subunit, was significantly higher in grade IV than in grade III and grade I/II tumors, and a statistical significant negative correlation between expression of ING-4 and expression of nuclear p65 was noticed. MMP-9, MMP-2 and u-PA were overexpressed in human astrocytomas. Of note, astrocytomas of advanced histologic grades (grade III, IV) displayed significantly higher expression levels of these proteins compared to tumors of lower grades (grade I, II). Collectively, our data suggest an essential role for ING-4 in human astrocytoma development and progression possibly through regulation of the NF-kappaB-dependent expression of genes involved in tumor invasion.

A case of complete androgen insensitivity syndrome presenting with incarcerated inguinal hernia: an immunohistochemical study.

OBJECTIVE: To present a case of complete androgen insensitivity syndrome that initially presented as incarcerated inguinal hernia and to investigate the expression of antimüllerian hormone (AMH), SOX-9 (SRY-box-containing gene 9), prostaglandin D synthase (PGDS), and androgen receptors (AR). DESIGN: Case report. SETTING: District hospital. PATIENT(S): A 12-year-old girl with negative past medical and family history, who presented with a 6-hour history of progressive left groin pain. INTERVENTION(S): Open gonadectomy. MAIN OUTCOME MEASURE(S): Immediate surgery, diagnosis, and referral to a multidisciplinary team for further management. RESULT(S): Pathologic analysis revealed a left twisted and infarcted testicle, and a normal right one containing immature seminiferous tubules with a decreased number of spermatogonia. Immunohistochemical analysis revealed strong cytoplasmic and nuclear expression of AMH and SOX-9, respectively, by the Sertoli cells as well as focal weak cytoplasmic PGDS expression. The spermatogonia showed focal weak nuclear PGDS expression. The Leydig cells showed no immunoreactivity at all. No AR immunoreactivity was observed. CONCLUSION(S): Negative AR immunostaining could either reflect Sertoli-cell immaturity or a mutation resulting in no protein production. The AMH immunodetection, consistent with its high serum levels, could potentially reflect Sertoli-cell immaturity. The SOX-9 nuclear detection in the Sertoli cells was consistent with its role, inducing male sex differentiation, including AMH expression. The nuclear localization of PGDS in the spermatogonia needs further investigation.

Coordinated upregulation of COX-2 and NF-kappaB is a steady feature of laryngeal carcinogenesis.

BACKGROUND/AIMS: Laryngeal cancer is the endpoint of a multistage process involving hyperplastic and dysplastic lesions, not adequately defined in their molecular aspect. Our objective was to evaluate the expression of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) and the chief transcription factor nuclear factor-kappaB (NF-kappaB) in laryngeal carcinomas and their precursors, as well as to explore any association between the two molecules. METHODS: We performed paraffin section immunohistochemistry for COX-2 and the p65 subunit of NF-kappaB, in tissues from 129 patients with tumors or premalignancies. p65 cytoplasmic and nuclear immunostaining were listed individually. RESULTS: COX-2 was positively correlated with histopathological grading from normal mucosa to carcinomas (Spearman's coefficient r(s) = 0.286, p < 0.001). No association was revealed between COX-2 expression and tumor grade. p65 immunoreactivity, both of cytoplasmic and nuclear origin, increased along the carcinogenesis course, manifesting highest expression in invasive cancer (r(s) = 0.419, p < 0.001 and r(s) = 0.241, p < 0.001, respectively). Again, tumor grade had no influence on expression. COX-2 and p65 cytoplasmic, but no nuclear, expression showed a positive correlation (r(s) = 0.352, p < 0.001). CONCLUSIONS: This study demonstrates that lesional advance in the larynx towards cancer is marked by ongoing upregulation of COX-2 and NF-kappaB. Synchronism between individual expressions may denote a regulatory role of the latter in COX-2 transactivation.