Non-Hodgkin lymphoma of the female genital tract mimicking primary gynecological tumors: a single-center series of 3 cases.

INTRODUCTION: Malignant lymphoma of the female genital tract is quite rare and its presentation may resemble that of other, more common tumors, causing confusion for clinicians. CASE HISTORY: The authors report three patients with a non-Hodgkin lymphoma (NHL) involving the female genital tract: two cases involved the ovary and one involved the uterus. In all patients, the genital tract was the initial site of clinical presentation of a B cell lymphoma. One patient was diagnosed postoperatively and subsequently received chemotherapy; the other two patients were diagnosed by imaging-guided biopsy and were successfully managed by chemotherapy without resection surgery. Two patients were alive, without evidence of disease, and one patient was alive with disease at their most recent follow-up visit. CONCLUSION: The authors' experience emphasizes that lymphoma should be in the differential diagnosis of pelvic gynecological malignancies, and its clinical, biological, and radiological signs must be actively sought. Imaging-guided biopsy should be performed to avoid unnecessary surgery.

Inhibition of temporomandibular joint input to medullary dorsal horn neurons by 5HT3 receptor antagonist in female rats.

Repeated forced swim (FS) conditioning enhances nociceptive responses to temporomandibular joint (TMJ) stimulation in female rats. The basis for FS-induced TMJ hyperalgesia remains unclear. To test the hypothesis that serotonin 3 receptor (5HT3R) mechanisms contribute to enhanced TMJ nociception after FS, ovariectomized female rats were treated with estradiol and subjected to FS for three days. On day 4, rats were anesthetized with isoflurane and TMJ-responsive neurons were recorded from superficial and deep laminae at the trigeminal subnucleus caudalis/upper cervical (Vc/C1-2) region and electromyographic (EMG) activity was recorded from the masseter muscle. Only Vc/C1-2 neurons activated by intra-TMJ injections of ATP were included for further analysis. Although neurons in both superficial and deep laminae were activated by ATP, only neurons in deep laminae displayed enhanced responses after FS. Local application of the 5HT3R antagonist, ondansetron (OND), at the Vc/C1-2 region reduced the ATP-evoked responses of neurons in superficial and deep laminae and reduced the EMG response in both sham and FS rats. OND also decreased the spontaneous firing rate of neurons in deep laminae and reduced the high-threshold convergent cutaneous receptive field area of neurons in superficial and deep laminae in both sham and FS rats. These results revealed that central application of a 5HT3R antagonist, had widespread effects on the properties of TMJ-responsive neurons at the Vc/C1-2 region and on jaw muscle reflexes under sham and FS conditions. It is concluded that 5HT3R does not play a unique role in mediating stress-induced hyperalgesia related to TMJ nociception.

Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye.

Dry eye (DE) disease is commonly associated with ocular surface inflammation, an unstable tear film and symptoms of irritation. However, little is known about the role of central neural mechanisms in DE. This study used a model for persistent aqueous tear deficiency, exorbital gland removal, to assess the effects of mustard oil (MO), a transient receptor potential ankyrin (TRPA1) agonist, on eyeblink and eyewipe behavior and Fos-like immunoreactivity (Fos-LI) in the trigeminal brainstem of male rats. Spontaneous tear secretion was reduced by about 50% and spontaneous eyeblinks were increased more than 100% in DE rats compared to sham rats. MO (0.02-0.2%) caused dose-related increases in eyeblink and forelimb eyewipe behavior in DE and sham rats. Exorbital gland removal alone was sufficient to increase Fos-LI at the ventrolateral pole of trigeminal interpolaris/caudalis (Vi/Vc) transition region, but not at more caudal regions of the trigeminal brainstem. Under barbiturate anesthesia ocular surface application of MO (2-20%) produced Fos-LI in the Vi/Vc transition, in the mid-portions of Vc and in the trigeminal caudalis/upper cervical spinal cord (Vc/C1) region that was significantly greater in DE rats than in sham controls. MO caused an increase in Fos-LI ipsilaterally in superficial laminae at the mid-Vc and Vc/C1 regions in a dose-dependent manner. Smaller, but significant, increases in Fos-LI also were seen in the contralateral Vc/C1 region in DE rats. TRPA1 protein levels in trigeminal ganglia from DE rats ipsilateral and contralateral to gland removal were similar. Persistent tear reduction enhanced the behavioral and trigeminal brainstem neural responses to ocular surface stimulation by MO. These results suggested that TRPA1 mechanisms play a significant role in the sensitization of ocular-responsive trigeminal brainstem neurons in this model for tear deficient DE.

Morphological and functional changes in regenerated primary afferent fibres following mental and inferior alveolar nerve transection.

BACKGROUND: It is important to know the mechanisms underlying pain abnormalities associated with inferior alveolar nerve (IAN) regeneration in order to develop the appropriate treatment for orofacial neuropathic pain patients. However, peripheral mechanisms underlying orofacial pain abnormalities following IAN regeneration are not fully understood. METHODS: Head withdrawal threshold (HWT), jaw opening reflex (JOR) thresholds, single-fibre recordings of the regenerated mental nerve (MN) fibres, calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), peripherin, neurofilament-200 (NF-200) and transient receptor potential vanilloid 1 (TRPV1) expression in trigeminal ganglion (TG) cells, and electron microscopic (EM) observations of the regenerated MN fibres were studied in MN- and IAN-transected (M-IANX) rats. RESULTS: HWT to mechanical or heat stimulation of the mental skin was significantly lower in M-IANX rats compared with sham rats. Mean conduction velocity of action potentials recorded from MN fibres (n = 124) was significantly slower in M-IANX rats compared with sham rats. The percentage of Fluoro-Gold (FG)-labelled CGRP-, peripherin- or TRPV1-immunoreactive (IR) cells was significantly larger in M-IANX rats compared with that of sham rats, whereas that of FG-labelled IB4- and NF-200-IR cells was significantly smaller in M-IANX rats compared with sham rats. Large-sized myelinated nerve fibres were rarely observed in M-IANX rats, whereas large-sized unmyelinated nerve fibres were frequently observed and were aggregated in the bundles at the distal portion of regenerated axons. CONCLUSIONS: These findings suggest that the demyelination of MN fibres following regeneration may be involved in peripheral sensitization, resulting in the orofacial neuropathic pain associated with trigeminal nerve injury.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following chemotherapy (paclitaxel and carboplatin) and radiation therapy in ovarian cancer: a case report.

In recent years, the incidence of therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML) that occur during chemotherapy for ovarian cancer has increased. While alkylating agents and topoisomerase II inhibitors are particularly mutagenic and have strong leukemogenic potential, paclitaxel and combination chemotherapy/radiation therapy also appear to induce t-MDS. The present authors report a case of t-MDS that developed during chemotherapy and radiation therapy for ovarian cancer. The patient was a 75-year-old woman who received six courses of cyclophosphamide/doxorubicin/cisplatin (CAP) therapy after initial surgery for Stage IIIc grade ovarian cancer in 1995. Beginning in February 2005, the patient experienced multiple recurrences due to sternal metastasis. Chemotherapy, including paclitaxel and carboplatin (TC), was administered intermittently and was combined with radiation therapy to a sternal metastatic lesion. Pancytopenia was observed in December 2008, and she was diagnosed with t-MDS (WHO subtype, refractory cytopenias with multilineage dysplasia [RCMD]): the time from first chemotherapy to t-MDS onset was 106 months. Without evidence of blast crisis, the recurrent lesions continued to grow and caused multiple cerebral infarctions, from which she eventually died. The cumulative doses of paclitaxel and carboplatin administered to this patient were 1,968 mg and 6,480 mg, respectively.

Surgical treatment outcomes of serious chronic tubo-ovarian abscess: a single-center series of 20 cases.

In recent years, Shimane University Hospital has begun to see patients with pelvic inflammatory disease (PID) which has become severe and chronic after insufficient conservative treatment in primary or secondary medical care facilities. Serious chronic tubo-ovarian abscess (TOA) is complicated by intraperitoneal inflammatory adhesions to surrounding organs, so that it is difficult to determine the original anatomical position of organs at surgery. Forcible synechotomy can result in damage to the adhering organs and insufficient drainage after surgery can cause recurrence of inflammation. In order to increase the chances for a successful surgical treatment, careful preparation, such as preoperative administration of antibiotics and ureteral stent insertion are necessary. In addition, the chances for recurrence of inflammation can be lessened by thorough intraperitoneal irrigation and insertion of a drainage tube.

Posterior hypothalamic modulation of light-evoked trigeminal neural activity and lacrimation.

Enhanced light sensitivity is a common feature of many neuro-ophthalmic conditions and some chronic headaches. Previously we reported that the bright light-evoked increases in trigeminal brainstem neural activity and lacrimation depended on a neurovascular link within the eye (Okamoto et al., 2012). However, the supraspinal pathways necessary for these light-evoked responses are not well defined. To assess the contribution of the posterior hypothalamic area (PH), a brain region closely associated with control of autonomic outflow, we injected bicuculline methiodide (BMI), a GABAa receptor antagonist, into the PH and determined its effect on the encoding properties of ocular neurons at the ventrolateral trigeminal interpolaris/caudalis transition (Vi/Vc) and caudalis/upper cervical cord junction (Vc/C1) regions and on reflex lacrimation in male rats under isoflurane anesthesia. BMI markedly reduced light-evoked (>80%) responses of Vi/Vc and Vc/C1 neurons at 10 min with partial recovery by 50 min after injection. BMI also reduced (>35%) the convergent cutaneous receptive field area of Vi/Vc and Vc/C1 ocular neurons indicating that both intra-ocular and periorbital cutaneous inputs were affected by changes in PH outflow. Light-evoked lacrimation was reduced by >35% at 10 min after BMI, while resting mean arterial pressure increased promptly and remained elevated (>20 mmHg) throughout the 50-min post-injection period. These results suggested that PH stimulation, acting in part through increased sympathetic activity, significantly inhibited light- and facial skin-evoked activity of ocular neurons at the Vi/Vc and Vc/C1 region. These data provide further support for the hypothesis that autonomic outflow plays a critical role in mediating light-evoked trigeminal brainstem neural activity and reflex lacrimation.

Fatty acid synthase expression associated with NAC1 is a potential therapeutic target in ovarian clear cell carcinomas.

BACKGROUND: This study examined the clinical significance of NAC1 and the expression level of its potential downstream target fatty acid synthase (FASN) in ovarian clear cell carcinomas (OCCCs), and evaluated the NAC1/FASN pathway as a potential therapeutic target. METHODS: NAC1 and FASN expression and NACC1 gene amplification were assessed in ovarian cancers by immunohistochemistry, fluorescence in situ hybridisation, and clinical data collected by a retrospective chart review. C75, a FASN inhibitor, was used to assess whether this pathway represented a therapeutic target in OCCC. RESULTS: High NAC1 expression was most frequent in clear cell tumours (40.0%:24/60). NACC1 gene amplification was identified in none of the 58 OCCCs. The frequency of NACC1 gene amplification was significantly higher in the high-grade serous histology than in the clear cell histology (P<0.01). NAC1 expression was significantly correlated with FASN expression in both OCCC samples and OCCC cell lines. Either high NAC1 expression or high FASN expression significantly correlated with shorter progression-free and overall survival (P=0.002 and 0.0048). NAC1 overexpression stimulated FASN expression, and NAC1 silencing using siRNA decreased FASN expression in OCCC cell lines. Profound growth inhibition was observed in C75-treated carcinoma cells with FASN overexpression when compared with the response in carcinoma cells without FASN expression. CONCLUSION: These findings indicate that NAC1/FASN overexpression is critical to the growth and survival of a subset of OCCC. The FASN silencing by the C75-induced phenotypes depends on the expression status of the targeted cell line. Therefore, NAC1/FASN pathway-targeted therapy may benefit selected OCCC patients.

Preserved autonomic function in patients with POEMS syndrome.

AIM: We systematically performed autonomic testing on patients with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS) to determine whether autonomic function is preserved in such patients. METHODS: We studied 17 POEMS patients, 17 diabetic neuropathy (DN) patients and 17 age-matched normal subjects. Blood pressure responses to the head-up tilt test and heart rate variability were used to evaluate cardiovascular autonomic function. Sweat responses and cutaneous vasoconstriction to several stimuli were recorded via the finger tips to estimate cutaneous sympathetic function. In addition, motor nerve conduction studies were performed. RESULTS: Although the results of the autonomic testing were normal in POEMS patients, motor disability was severe, and motor nerve conduction studies provided evidence of extensive axonal loss. The DN patients showed significantly impaired autonomic responses despite mild motor dysfunction. CONCLUSIONS: Autonomic function was normal in POEMS patients, indicating the preservation of autonomic fibers and selective involvement of large fibers.

EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target.

BACKGROUND: The aim of this study was to investigate the patterns of epidermal growth factor receptor (EGFR) overexpression, EGFR gene amplification, and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the uterine cervix. METHODS: The EGFR expression, amplification, and mutation in cervical carcinomas were assessed by immunohistochemistry, fluorescence in situ hybridisation, and PCR-SSCP, respectively, and correlated with clinical data collected by a retrospective chart review. A functional assessment was performed by inactivating EGFR in cervical cancer cells with the potent inhibitor AG1478. RESULTS: Immunohistochemical analysis revealed that 6 out of 59 (10.2%) cervical squamous cell carcinomas showed significant amplification of the EGFR locus, whereas none of the 52 adeno/adenosquamous cell carcinomas had detectable EGFR amplification (P<0.05). The EGFR amplification significantly correlated with shorter overall survival (P=0.001) in cervical squamous cell carcinomas. Multivariate analysis showed that EGFR gene amplification was an independent prognostic factor for overall survival (P=0.011). None of the squamous cell carcinomas (0%: 0 out of 32) had detectable oncogenic mutations in EGFR exons 18 through 21. The frequencies of KRAS and BRAF mutations were very low in both squamous and adeno/adenosquamous cell carcinomas. Sensitivity of cervical cancer cells to AG1478 depended on the presence of EGFR overexpression. AG1478-induced EGFR inactivation in cell lines with EGFR overexpression significantly suppressed tumour development and progression in a mouse xenograft model. CONCLUSION: Our data suggest that EGFR signalling is important in a subset of cervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11.2 amplicon in their tumours.

A comparative study between microwave endometrial ablation and conventional surgical procedures for treatment of menorrhagia.

OBJECTIVE: To compare microwave endometrial ablation (MEA) using a new curved applicator with conventional surgical procedures in 26 patients with menorrhagia. STUDY DESIGN: Ten patients received MEA and 16 patients received conventional surgical procedures. Using a visual analog scale (VAS). MEA patients rated their menorrhagia, dysmenorrhea, and feelings of satisfaction from the procedure. The patients' intraoperative blood loss, operating time, and length of hospital stay were compared. RESULTS: Following MEA, the VAS scores were significantly decreased in the MEA patients for menorrhagia (p < 0.0001) and dysmenorrhea (p = 0.0002). The average VAS score regarding feelings of satisfaction for MEA was 8.9 (full score = 10). Mean blood loss, operating time, and mean length of hospital stay were significantly decreased in the MEA group compared to the conventional surgical procedure group (p < 0.0001). CONCLUSION: MEA successfully controlled menorrhagia and achieved a high rate of satisfaction among patients.

Exaggerated placental site mimicking placental site trophoblastic tumor: case report and literature review.

Exaggerated placental site is defined as a non-neoplastic trophoblastic lesion featuring exuberant infiltration into the endometrium and myometrium by intermediate trophoblasts and syncytiotrophoblasts. Exaggerated placental site can occur following normal or ectopic pregnancy, abortion, or hydatidiform mole. We encountered a case of reactive exaggerated placental site seven months following normal pregnancy that clinically mimicked placental site trophoblastic tumor. Few reports have described the clinical course, histopathology and differential diagnosis of exaggerated placental site; we present our patient's case together with histopathological observations and review of related literature.

A case of extremely chemoresistant pure pleomorphic rhabdomyosarcoma of the uterus associated with a high serum LDH level.

BACKGROUND: Pleomorphic rhabdomyosarcoma (RMS) of gynecologic origin is an exceedingly rare, highly malignant tumor. Only a few cases have been reported in the last decades. CASE REPORT: A 60-year-old postmenopausal woman presented with a high LDH level of unknown origin. Ultimately, she was diagnosed with pleomorphic RMS. She underwent total hysterectomy, bilateral salpingo-oophorectomy, left pelvic and paraaortic lymphadenectomy and partial omentectomy. Surgery was followed by systemic chemotherapy and pelvic irradiation. Unfortunately, the patient did not respond to treatment. Her disease course correlated with the fluctuation of plasma LDH levels. Ultimately she died within 20 months of the diagnosis. CONCLUSION: It is important to have better insight and to set a standard multimodal treatment for adult RMS. In addition, plasma LDH levels can be considered as a prognostic marker for RMS, particularly in advanced stage.

KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer.

This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (P<0.001), and p-ERK1/2 (P<0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P=0.2460, P=0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.

Narrow band imaging with magnifying colonoscopy as diagnostic tool for predicting histology of early colorectal neoplasia.

BACKGROUND: The presence of abnormal microcapillaries detected by narrow band imaging (NBI) with magnifying colonoscopy has been reported to be a marker of colorectal neoplasia. AIM: To investigate prospectively if NBI with magnification could help predict the histology of early colorectal neoplasia. METHODS: A series of 104 consecutive patients with 139 colorectal lesions were studied. All lesions were detected by conventional colonoscopy and subsequently evaluated by NBI with magnification. During NBI with magnification, the microvascular architecture observed on the surface of the detected lesions, capillary patterns (CP), was divided into non-neoplastic (CP I) and neoplastic (CP II and CP III) types. Only lesions endoscopically diagnosed as CP II or CP III were included in the study. All of the lesions were resected endoscopically or surgically and examined histologically for comparison. RESULTS: Ninety-seven per cent (n = 103) of colorectal neoplastic lesions with CP II were histologically diagnosed as low-grade dysplasia. Eighty-seven per cent (n = 31) of the colorectal neoplastic lesions with CP III were high-grade dysplasia or invasive cancer. CONCLUSION: Capillary patterns observed by NBI with magnification could be used to assess the degree of atypia in early colorectal neoplasia.

Therapy-related myelodysplasia and acute myeloid leukemia following paclitaxel- and carboplatin-based chemotherapy in an ovarian cancer patient: a case report and literature review.

Alkylating agents have strong leukemogenic potential. There are a number of recent acute myeloid leukemia (t-AML) cases related to previous paclitaxel exposure. These leukemias tend to be of aggressive subtypes with long-latency periods. Unlike previously reported cases, the present case was of the secondary acute megakaryoblastic myeloid leukemia (AML M7) subtype. Additionally, it did not harbor a translocation in chromosome 19. A 73-year-old woman was diagnosed with t-AML M7 with antecedent myelodysplasia. Leukemia followed a second induction of paclitaxel- and carboplatin-based chemotherapy for recurrent ovarian cancer. Her second induction began 25 months after completion of her first course of chemotherapy. The increased incidence of postpaclitaxel leukemia suggests a probable role for paclitaxel as a leukemogenic agent. It highlights the importance of assessing for leukemia risk factors prior to beginning paclitaxel therapy.

Striking alteration of some populations of T/B cells in systemic lupus erythematosus: relationship to expression of CD62L or some chemokine receptors.

Recent studies have revealed new populations of T/B cells, including central/effector memory, follicular T cells and CXCR3+ or CXCR4+ B cells. In the present study, changes in these populations of CD4+ T cells were examined on the basis of the expression of CD62L, CCR7 and CXCR5 in patients with systemic lupus erythematosus (SLE) in relation to CCL21 and CXCL10. Changes in CXCR3+, CXCR4+ and CXCR5+ B cells were also examined. CD62L and various chemokine receptors were examined by flow cytometry analysis using monoclonal antibodies, and CCL21 and CXCL10 were examined by sandwich enzyme-linked immunosorbent assay. In patients with SLE, a decrease of naive T cells and an increase in the ratio of activated effector memory T cells were associated with an increase of CCL21 and CXCL10 in serum, although the correlation was not significant. An increase in the ratio of CXCR3+ B cells was also recognized. These results suggest that naive T cells are transferred to lymphoid tissue by CCL21, and that effector memory T cells are activated by CXCL10. It is also suggested that B cells responsive to follicular helper T cells tend to migrate to inflammatory tissue.

Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas.

Interleukin (IL)-1 gene polymorphisms are associated with development of gastric atrophy and with increased risk of gastric carcinoma. A -31C to T base transition in the promoter region of this gene is involved in carcinogenic changes within the stomach, especially in Helicobacter pylori infected individuals. We examined association between IL-1 locus polymorphisms and risk of esophageal, gastric and colorectal carcinomas in Japanese patients with H. pylori infection. IL-1B and IL-1RN polymorphisms were analyzed in 136 controls, 75 patients with esophageal carcinoma, 186 patients with gastric carcinoma, 69 patients with colorectal carcinoma, and 18 patients with ulcerative colitis (UC). For IL-1B-511 and -31 polymorphisms were determined by fluorescence-based polymerase chain reaction single-strand conformation polymorphism analysis. For IL-1 receptor antagonist gene (IL-1RN), penta-allelic variable number of tandem repeats (VNTR) was determined by PCR-standard agarose gel electrophoresis. For gastric carcinoma, IL-1B-511 heterozygotes (OR, 0.48; 95% CI, 0.3-0.9; p=0.0115) and T carriers (OR, 0.52; 95% CI, 0.3-1.0; p=0.0185) had a significantly reduced risk of carcinoma. For colorectal carcinoma, IL-1B-511 heterozygotes (OR, 0.34; 95% CI, 0.2-0.7; p=0.0028) and T carriers (OR, 0.43; 95% CI, 0.2-0.9; p=0.0015) had a significantly low risk of carcinoma. No significant difference was observed in the frequencies of IL-1B-31C/T and IL-1RN genotypes between controls and the esophageal carcinoma patients. Our results shows that IL-1B-511C/T and T carrier state may indicate less risk for gastric and colorectal carcinoma in the Japanese population.

Study of p53 gene alteration as a biomarker to evaluate the malignant risk of Lugol-unstained lesion with non-dysplasia in the oesophagus.

Mutations of the p53 gene are detected frequently in oesophageal dysplasia and cancer. It is unclear whether Lugol-unstained lesions (LULs) with non-dysplastic epithelium (NDE) are precursors of oesophageal squamous cell carcinoma (ESCC). To study the genetic alterations of NDE in the multistep process of oesophageal carcinogenesis, we determined the relationship between p53 mutations and LULs-NDE. Videoendoscopy with Lugol staining was performed prospectively in 542 oesophageal cancer-free subjects. Lugol-unstained lesions were detected in 103 subjects (19%). A total of 255 samples, including 152 LULs (NDE, 137; dysplasia, 15) and 103 paired samples of normal staining epithelium, were obtained from 103 subjects. After extraction of DNA and polymerase chain reaction analysis, direct sequencing method was applied to detect mutations of the p53 gene. The p53 mutation was detected in five of 137 samples with LULs-NDE (4%) and in five of 15 samples with dysplasia (33%). A hotspot mutation was found in 20% of LULs-NDE with p53 mutation and in 40% of dysplasia with p53 mutation. In contrast, no p53 mutations were found in 103 paired NDE samples with normal Lugol staining. In biopsy samples from oesophageal cancer-free individuals, the p53 missense mutations containing a hotspot mutation were found in NDE, which was identified as an LUL. These findings suggest that some LULs-NDE may represent the earliest state of oesophageal squamous cell carcinoma in Japanese individuals.