Spectroscopic evaluation of carcinogenesis in endometrial cancer.

Carcinogenesis is a multifaceted process of cancer formation. The transformation of normal cells into cancerous ones may be difficult to determine at a very early stage. Therefore, methods enabling identification of initial changes caused by cancer require novel approaches. Although physical spectroscopic methods such as FT-Raman and Fourier Transform InfraRed (FTIR) are used to detect chemical changes in cancer tissues, their potential has not been investigated with respect to carcinogenesis. The study aimed to evaluate the usefulness of FT-Raman and FTIR spectroscopy as diagnostic methods of endometrial cancer carcinogenesis. The results indicated development of endometrial cancer was accompanied with chemical changes in nucleic acid, amide I and lipids in Raman spectra. FTIR spectra showed that tissues with development of carcinogenesis were characterized by changes in carbohydrates and amides vibrations. Principal component analysis and hierarchical cluster analysis of Raman spectra demonstrated similarity of tissues with cancer cells and lesions considered precursor of cancer (complex atypical hyperplasia), however they differed from the control samples. Pearson correlation test showed correlation between cancer and complex atypical hyperplasia tissues and between non-cancerous tissue samples. The results of the study indicate that Raman spectroscopy is more effective in assessing the development of carcinogenesis in endometrial cancer than FTIR.

Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder: a clinicopathologically distinct, invasion-resistant entity.

Preinvasive tumor-forming gallbladder neoplasms that are composed of small, non-mucinous tubules with complex architecture remain a poorly characterized group. Here, we evaluated the clinicopathological characteristics of this entity. Twenty-eight examples were analyzed. Tumors were invariably pedunculated polyps with thin stalks, often presented as loosely attached intraluminal nodules, with cauliflower architecture (akin to cholesterol polyps) comprised of compact, back-to-back acinar-like, small tubular units with minimal/no cytoplasm showing variable complexity, creating a picture distinct from the other tubular type dysplasia in the gallbladder. Their limited stroma showed distinctive amorphous amyloid-like hyalinization (39%). While some had round nuclei with single prominent nucleoli, others exhibited slightly more elongated nuclei with washed out chromatin reminiscent of papillary thyroid carcinoma. Squamoid/meningothelial-like morules (71%) and subtle neuroendocrine cell clusters (39%) were frequent. The level of cytoarchitectural atypia qualified as high-grade dysplasia (HGD) in all cases, but none were invasive. The background mucosa showed no dysplasia, but cholesterolosis. The majority (n = 8/12) showed diffuse MUC6 expression and lacked MUC5AC expression. Based on these observations, 635 gallbladder carcinomas were re-analyzed for residual/adjacent lesions with entity-defining characteristics disclosed here, and none could be identified. Preinvasive tubular non-mucinous neoplasm of the gallbladder, which we propose to classify as intracholecystic tubular non-mucinous neoplasm, is a clinicopathologically discrete entity, which tends to occur in uninjured gallbladders and in association with cholesterol polyps. By being tubular, non-mucinous and MUC6-positive, it is akin to intraductal tubulopapillary neoplasms of pancreatobiliary tract, but it is also different in many other aspects. Although their cytoarchitectural complexity warrants an HGD/carcinoma classification, they do not show invasion and their distinct characteristics warrant their separate classification.

Feasibility of Voltage-Applied SERS Measurement of Bile Juice as an Effective Analytical Scheme to Enhance Discrimination between Gall Bladder (GB) Polyp and GB Cancer.

A unique surface-enhanced Raman scattering (SERS) measurement scheme to discriminate gall bladder (GB) polyp and GB cancer by analysis of bile juice is proposed. Along with the high sensitivity of SERS, external voltage application during SERS measurement was incorporated to improve sample discriminability. For this purpose, Au nanodendrites were constructed on a screen-printed electrode (referred to as AuND@SPE), and Raman spectra of extracted aqueous phases from raw bile juice samples were acquired using the AuND@SPE at voltages from -300 to 300 mV. The sample spectra resembled that of bilirubin, possessing an open chain tetrapyrrole, showing that bilirubin derivatives in bile juice were mainly responsible for the observed peaks. Discrimination of GB polyp and GB cancer using just the normal SERS spectra was not achieved but became apparent when the spectra were acquired at a voltage of -100 mV. When voltage-applied SERS spectra of bilirubin and urobilinogen (one of bilirubin's derivatives) were examined, a sudden intensity elevation occurring at -100 mV was observed for urobilinogen but not bilirubin. Based on examination of corresponding cyclic voltammograms, the potential-driven strong adsorption of urobilinogen (no faradaic charge transfer) on AuND occurring at -100 mV induced a substantial increase in SERS intensity. It was presumed that the content of urobilinogen in the bile juice of a GB cancer patient would be higher than that of a GB polyp patient, and the contained urobilinogen was sensitively highlighted by applying -100 mV during SERS measurement, allowing clear discrimination of GB cancer against GB polyp.

MyoD1 expression in fibroepithelial stromal polyps.

Fibroepithelial stromal polyps (FESPs) are benign polypoid mesenchymal lesions thought to arise from desmin-positive specialized stromal cells of the female genital tract. Although most cases are easily diagnosed by morphology alone, the morphology of FESPs is variable and in some instances can contain hypercellular stroma with numerous atypical desmin-positive cells, simulating botryoid embryonal rhabdomyosarcoma (ERMS). Recently, we encountered a cellular FESP showing desmin expression as well as nuclear immunoreactivity for the skeletal muscle-associated transcription factor MyoD1. Although these lesions are widely known to express desmin, there are very few studies examining expression of the more specific markers of skeletal muscle differentiation, myogenin and MyoD1. The aim of our study was to examine desmin, MyoD1, and myogenin expression in a series of 25 FESPs. Of the 25 cases, desmin expression was present in 23 (92%), at least focal MyoD1 expression was present in 10 (40%), and all cases were negative for myogenin. Follow-up data were available for all 25 cases, and none recurred or behaved in a malignant fashion. Awareness of this potential immunohistochemical pitfall and careful morphologic evaluation should allow for the confident distinction of MyoD1-positive FESP from botyroid ERMS in almost all instances.

Factors associated with endometrial pathology during tamoxifen therapy in women with breast cancer: a retrospective analysis of 821 biopsies.

PURPOSE: This study evaluated the factors associated with endometrial pathologies during tamoxifen use in women with breast cancer. METHODS: This study analyzed 821 endometrial biopsies from women who received tamoxifen for breast cancer. Clinical characteristics were compared according to the presence of endometrial pathology (atypical hyperplasia and cancer). In addition, patients with endometrial polyps were compared with women with normal histology. RESULTS: Among 821 biopsies, atypical endometrial hyperplasia and cancer were diagnosed in 7 women each. Endometrial polyps were found in 173 women, and 634 women presented normal histology. In comparing women with endometrial pathology (atypical hyperplasia and cancer, n = 14) and those without pathology, parity was significantly lower (P = 0.014) and endometrial thickness was significantly higher (P < 0.001) in women with pathology. In addition, abnormal uterine bleeding was more common in the pathology group (P < 0.001). However, age, body mass index, menopausal status, intrauterine device use, history of diabetes mellitus, and duration of tamoxifen use did not differ according to the presence of pathology. In comparing women with endometrial polyps and those with normal endometrium, significant differences were found in parity (P < 0.001), duration of tamoxifen use (P = 0.003), and endometrial thickness (P < 0.001), but not in the presence of abnormal vaginal bleeding. CONCLUSION: Parity, endometrial thickness, and the presence of abnormal vaginal bleeding, but not age, body mass index, and menopausal status, may be associated with endometrial pathology during tamoxifen use in women with breast cancer. This finding might provide useful information for gynecological surveillance and counseling during tamoxifen treatment.

Dilated Minute Chambers in Laryngeal Vocal Fold Polyps: Histopathological and Ultrastructural Features.

In Reinke's space of human vocal fold, type III collagen forms a three dimensional network and this contains numerous minute chambers in between these fibers. These compartments are occupied by glycosaminoglycans and glycoproteins. In laryngeal fold lesions, such as Reinke's edema and vocal fold polyps, proteoglycan (PG)/hyaluronic acid (HA) components of extracellular matrix increased. We investigated the size and quantity of the minute chambers within Reinke's space, filled with PG/HA with the aid of transmission electron microscopy. Eight vocal fold polyps and 10 mucosal biopsies (as control group) were all evaluated by light microscopy and electron microscopy. We detected that PG/HA in extracellular matrix had been increased in vocal fold lesions when compared with control group, by Alcian Blue-pH 2.5 stain. The mean volume of the chambers in Reinke's space of normal larynx was measured as 0.040233 µm2 whereas the mean volume of these chambers in vocal fold polyps was measured as 6.420221 µm2. The difference between the volumes of these chambers in vocal fold polyps and in control group was statistically significant (P = 0.001). Within these chambers PG/HA were found and PG/HA filling these chambers were increased in vocal fold polyps. We think proteoglycan and glycosaminoglycans, especially HA, play an important role in determining biochemical properties of vocal fold lesions.

Non-neoplastic Polyps of the Gallbladder: A Clinicopathologic Analysis of 447 Cases.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were ≥1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

SATB2 is Consistently Expressed in Squamous Morules Associated With Endometrioid Proliferative Lesions and in the Stroma of Atypical Polypoid Adenomyoma.

So-called squamous morules are closely associated with endometrioid proliferative lesions, in the endometrium and the ovary. Morules have an unusual immunophenoptype, typically exhibiting nuclear staining with ß-catenin, positivity with CDX2, CD10, and p16 and are negative with hormone receptors and p63. We report the previously undescribed occurrence of consistent SATB2 nuclear positivity within morules. Nuclear positivity was present in 38/43 (88%) cases of morules (24 focal; 14 diffuse) while all cases of nonmorular squamous metaplasia in endometrioid proliferative lesions (n=13) were SATB2 negative, except for occasional positive nuclei in 1 case. We also observed that the stromal cells of atypical polypoid adenomyoma typically exhibited diffuse nuclear immunoreactivity with SATB2 while the stromal cells of other endometrial polypoid lesions (endometrial polyp, adenomyoma, adenosarcoma) were usually negative, although there was focal weak staining in occasional cases. Pathologists should be aware of this previously undescribed phenomenon which represents a further example of the unusual immunophenotype of so-called squamous morules. The reasons underlying SATB2 nuclear positivity in squamous morules and the stroma of atypical polypoid adenomyoma are unknown.

Cholesterol granuloma in an antrochoanal polyp. A rare lesion in children.

Antrochoanal polyps (ACPs) are an infrequent clinical entity. Cholesterol granulomas (CGs) are commonly associated with chronic middle ear disease but are rare in the paranasal sinuses. We describe a case of a 10-year-old girl with a concomitant CG in an ACP which was surgically excised by nasosinusal endoscopic surgery. To our knowledge, there are only five previously published cases of CGs in ACPs and of these, only two were pediatric cases. We describe a third case in the youngest patient yet reported. Increased intrasinus pressure may affect venous and lymphatic drainage, leading to hemorrhages with hemolysis and deposition of cholesterol crystals and their esters initiating the formation of granulomas in the polyp. In addition, the insufficient lymphatic drainage prevents the complete elimination of lipids, contributing to the formation of cholesterol granulomas. The treatment and the outcome of an ACP associated with a CG are the same as for usual ACPs.

Cholesterol polyps in the distal common bile duct: a case report.

RATIONALE: Cholesterol polyps are rare in the common bile duct and difficult to diagnose. PATIENT CONCERNS: The small polypoid lesions often go undetected when using routine imaging methods, such as ultrasonography. DIAGNOSES: We treated a patient with cholesterol polyps in the common bile duct. After failing to detect choleliths using ultrasonography, magnetic resonance cholangiopancreatography revealed mild dilation of the common bile duct. Choledochoscopy was performed during laparoscopic cholecystectomy, which revealed yellowish-white polyps circumferentially distributed across the luminal surface of the distal common bile duct. Histological examination of biopsy specimens indicated cholesterol polyps with characteristic foamy cells. INTERVENTIONS: The patient was treated with ursodeoxycholic acid, and the number of polyps was found to have been reduced at the 6-week follow-up based on T-tube choledochoscopic examination. OUTCOMES: Recovery was unremarkable, and the ursodeoxycholic acid treatment was discontinued at the 6-month follow-up. LESSONS SUBSECTIONS: Our findings suggest that this rare condition can be treated pharmacologically to avoid potential postsurgical complications following resection of the distal common bile duct.

Expression of a disintegrin and metalloproteinase-33 protein in vocal fold polyps.

BACKGROUND: This study aimed to evaluate the association of a disintegrin and metalloproteinase-33 protein ('ADAM-33') expression in vocal polyp formation and to determine its correlation with clinical characteristics. METHODS: Medical charts and histological sections of 32 patients diagnosed with vocal polyps who underwent surgery were analysed. Controls were histopathologically normal vocal fold tissues obtained from 36 patients who underwent surgery for laryngeal squamous cell carcinoma. Immunohistochemical staining was performed to detect ADAM-33 expression in epithelial cells, stroma and vessels. RESULTS: All epithelial, stromal and vascular staining scores were significantly greater in polyp tissue than in controls (p < 0.001). Stromal ADAM-33 staining scores were higher in vocal polyp patients with a symptom duration of less than six months (p < 0.05). Vocal overuse or the presence of reflux symptoms, sinonasal symptoms or allergy did not affect ADAM-33 immunostaining scores (p = 0.05). CONCLUSION: In this study, ADAM-33 immunostaining was significantly increased in vocal polyps. Therefore, over-expression of this protein may be associated with vocal polyp pathogenesis.

Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins.

Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

Signet-ring cell carcinoma arising from a fundic gland polyp in the stomach.

Fundic gland polyps (FGPs) are currently the most common type of gastric polyps and are usually benign. However, although rare, gastric adenocarcinoma of FGP has been recently proposed as a new variant of gastric adenocarcinoma. Here we report the first case of a 49-year-old woman with focal signet ring cell carcinoma that arose from an FGP of the stomach. The tumor was completely excised by endoscopic snare polypectomy. FGPs should therefore be evaluated for malignant changes although they occur rarely, if the FGP has an erosive or irregular surface.

Uterine tumour resembling ovarian sex cord tumours presenting as multiple endometrial and cervical uterine polyps: a case report.

BACKGROUND: Uterine tumours resembling ovarian sex-cord tumours (UTROSCT) are very rare, benign uterine tumours, composed solely of sex cord elements. These tumours have a polyphenotypic immunophentype that favours a derivation from uterine mesenchymal stem cells. CASE REPORT: A 43-year-old female presented with recurrent vaginal bleeding. On hysteroscopy, she had multiple endometrial and cervical polyps that were removed endoscopically. Histologically, the specimen contained epithelioid cells arranged in tubules, trabeculae and anastomosing cords, without significant cellular atypia or mitotic activity. Immunohistochemical studies were performed. The tumour was found to be diffusely positive for vimentin, calretinin and desmin, focally positive for cytokeratin, CD99 and inhibin and negative for chromogranin and CD10. A subsequent total hysterectomy was performed and revealed neoplastic infiltration of the myometrium. CONCLUSION: A polyphenotypic immunophenotype is a characteristic feature of UTROSCT, and may be helpful in diagnosis and in exclusion of other lesions. Familiarity with this tumour by gynaecologists and pathologists is essential to avoid misdiagnosis:correct diagnosis of this neoplasm is important in patient management.

Prostate type epithelial polyps of urogenital tract: a series of 3 cases and literature review.

OBJECTIVE: To present clinicopathologic and immunohistochemical features of 3 cases of rare and unusual condition of urogenital tract, prostatic epithelial polyps situated in various parts of the urinary tract, with a heterogeneous presentation and a benign behavior. METHODS: Detailed data on 3 patients with polyps in the urinary tract presented from January 2008 to December 2012 were reviewed, and the clinicopathologic characteristics of the patients and disease along with various diagnostic and treatment modalities were recorded. RESULTS: All the 3 patients were aged older than 45 years. The presenting symptom hematuria was common to each patient. One patient had polypoidal growth in preprostatic (intramural) urethra; the other 2 had polyps in bladder. Each patient had other urogenital tract disease, 2 were known case of benign prostatic hyperplasia, and 1 had past history of urinary bladder carcinoma. Clinically, each of the case was misdiagnosed as aggressive lesions; however, after histopathologic diagnosis, management was undertaken according to benign result. No recurrence or metastasis was observed to date. Immunohistochemical stain prostate-specific antigen was positive in the epithelium. All 3 patients were recurrence-free on follow-up. CONCLUSION: The prostate type epithelial polyps are rare in urinary bladder and bladder urethra and are frequently associated with concurrent pathologies of urogenital tract. These are benign conditions with differential of other benign and malignant disorders.

Prognostic Value of the Stem Cell Markers Epcam and CD133 Expression Of Gallbladder Adenocarcinoma.

BACKGROUND/AIMS: To investigate the expressions and prognostic value of stem cell markers, EpCAM and CD133, in benign and malignant lesions of gallbladder. METHODOLOGY: Expression of EpCAM and CD133 was assessed in gallbladder adenocarcinoma (n = 100), peritumoral tissues (n = 46), adenoma (n = 30), polyp (n = 15), and chronic cholecystitis (n = 35) by using immunohistochemistry. RESULTS: The positive rates of EpCAM and CD133 expression were significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (χ2(EpCAM7) = 15.36, χ2(CD133) =16.05; Ps < 0.01), adenoma (χ2 (EpCAM) =10.92, χ2(CD133) = 11.09; Ps < 0.01), polyp (χ2(EpCAM) = 8.88, χ2(CD133) = 10.43; Ps < 0.01) and chronic cholecystitism (χ2(EpCAM) = 28.58, χ2(CD133) =25.57; Ps < 0.01). In adenocarcinoma, the positive expression of EpCAM and CD133 was significanctly associated with differentiation, tumor mass, lymph node metastasis, invasion and overall survival. Notably, the benign lesions with positive EpCAM or /and CD133 expression showed moderately or severely atypical hyperplasia in gallbladder epithelium. The high consistence was found between the expressive levels of EpCAM and CD133 in gallbladder adenocarcinoma (χ2 = 10.02, P < 0.01). Unitivariate Kaplan-Meier analysis showed that high level of EpCAM (P = 0.004) and CD133 (P = 0.012) were associated with poor overall survival. CONCLUSIONS: The elevated expression of EpCAM and/or CD133 is closely related to the carcinogenesis, progression, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.

A white opaque substance-positive gastric hyperplastic polyp with dysplasia.

The endoscopic findings of gastric hyperplastic polyps (HPs) with dysplasia have not been well-defined, and the clinical significance of these lesions, including their malignant potential, is unclear. In this report, we describe a case of a white opaque substance (WOS)-positive gastric HP with dysplasia. A 76-year-old woman was referred to our hospital for endoscopic resection of a gastric HP. Upper endoscopy revealed a 25-mm whitish and reddish polypoid lesion on the greater curvature in the lower third of the stomach. The whitish part was diagnosed as a WOS using conventional and magnifying endoscopy with narrow band imaging. An examination of the biopsy specimen indicated that the lesion was a typical gastric HP. However, because of its color and the presence of a WOS, we suspected that this lesion was an atypical gastric HP. Therefore, we performed a polypectomy. Histopathologically, diffuse low- to high-grade dysplasia was found on the surface of the polyp. We performed immunohistochemical staining using a monoclonal antibody specific for adipophilin as a marker of lipid droplets (LDs). LDs were detected in approximately all of the neoplastic cells, especially in the surface epithelium of the intervening apical parts and were located in the subnuclear cytoplasm of the neoplastic cells. According to endoscopic and histopathological findings, the WOS-positive epithelium indicated dysplasia of the gastrointestinal phenotype, which could absorb lipids. The presence of a WOS in a gastric HP may be considered an endoscopic finding that is predictive of the neoplastic transformation of a gastric HP. We suggest that a WOS-positive gastric HP should be resected endoscopically to investigate its neoplastic transformation.

Correlation of S1P1 and ERp29 expression to progression, metastasis, and poor prognosis of gallbladder adenocarcinoma.

BACKGROUND: Gallbladder cancer (GBC) is one of the most aggressive malignant neoplasms with an extremely poor prognosis. Early diagnosis significantly increases the survival rate. The present study was undertaken to evaluate the diagnostic and prognostic value of sphingosine-1-phosphate receptor 1 (S1P1) and endoplasmic reticulum protein 29 (ERp29) in benign and malignant gallbladder lesions and to develop a possible alternative treatment for GBC. METHODS: A total of 100 gallbladder adenocarcinoma, 46 peritumoral, 30 gallbladder adenomatous, 15 gallbladder polyp, and 35 chronic cholecystitis tissues were included. S1P1 and ERp29 expressions were evaluated by immunohistochemistry. The correlation between S1P1 and ERp29 expression and tumor pathological features and prognosis was analyzed. RESULTS: S1P1 positive rate was significantly higher in gallbladder adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. On the contrary, ERp29 positive rate was significantly lower in adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. Benign lesions with positive S1P1 or negative ERp29 expression showed moderate or severe atypical hyperplasia in the gallbladder epithelium. The overexpression of S1P1 or non-expression of ERp29 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis, and adenocarcinoma invasion. Univariate Kaplan-Meier analysis showed that the elevated S1P1 (P=0.008) or absence of ERp29 (P=0.043) was closely associated with decreased survival rate. Multivariate Cox regression analysis showed that S1P1 positive (P=0.004) or ERp29 negative (P=0.029) was an independent predictor of poor prognosis in gallbladder adenocarcinoma. CONCLUSION: S1P1 overexpression or ERp29 absence is related to the carcinogenesis and progression, and may be potential biomarkers for early detection of gallbladder adenocarcinoma.