Philip T. Valente

Elevated Expression of the Oncogene c-fms and Its Ligand, the Macrophage Colony-Stimulating Factor-1, in Cervical Cancer and the Role of Transforming Growth Factor-β1 in Inducing c-fms Expression

Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-beta1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer.

Significant reduction in the rate of false-negative cervical smears with neural network-based technology (PAPNET testing system)

False-negative cervical Pap smears may lead to disability or death from carcinoma of the uterine cervix. New computer technology has led to the development of an interactive, neural network-based vision instrument to increase the accuracy of cervical smear screening. The instrument belongs to a new class of medical devices designed to provide computer-aided diagnosis (CADx). To test the instruments performance, 487 archival negative smears (index smears) from 228 women with biopsy-documented high-grade precancerous lesions or invasive cervical carcinoma (index women) were retrieved from the files of 10 participating laboratories that were using federally mandated quality assurance procedures. Samples of sequential negative smears (total 9,666) were retrieved as controls. The instrument was used to identify evidence of missed cytological abnormalities, including atypical squamous or glandular cells of undetermined significance (ASCUS, AGUS), low-grade or high-grade squamous intraepithelial lesions (LSIL, HSIL) and carcinoma. Using the instrument, 98 false-negative index smears were identified in 72 of the 228 index women (31.6%, 95% confidence interval [CI]: 25% to 38%). Disregarding the debatable categories of ASCUS or AGUS, there were 44 women whose false-negative smears disclosed squamous intraepithelial lesions (SIL) or carcinoma (19.3%; 95% CI: 14.2% to 24.4%). Unexpectedly, SILs were also identified in 127 of 9,666 control negative smears (1.3%; 95% CI: 1.1% to 1.5%). Compared with historical performance data from several participating laboratories, the instrument increased the detection rate of SILs in control smears by 25% and increased the yield of quality control rescreening 5.1 times (P < 0.0001). These data provide evidence that conventional screening and quality control rescreening of cervical smears fail to identify a substantial number of abnormalities. A significant improvement in performance of screening of cervical smears could be achieved with the use of the instrument described in this report.

Up-regulation of VEGF, c-fms and COX-2 expression correlates with severity of cervical cancer precursor (CIN) lesions and invasive disease

OBJECTIVES To describe the expression of vascular endothelial growth factor (VEGF), proto-oncogene macrophage colony-stimulating factor receptor (c-fms) and cyclooxygenase-2 (COX-2) in cervical carcinogenesis and to analyze the correlation of VEGF with c-fms and COX-2 expression. METHODS In this study, 26 cases of benign cervix, 28 low-grade cervical intraepithelial neoplasia (CIN; CIN 1), 30 high-grade CIN (CIN 2/3) and 28 squamous cervical carcinomas (SCC) were examined by immunohistochemistry (IHC) and analysis was performed separately for epithelium and stroma. RESULTS Positive epithelial expressions in normal cervix, low-grade CIN, high-grade CIN and SCC were, respectively: VEGF - 11.5%, 39.3%, 53.3% and 75% (P<0.001); c-fms - 0%, 10.7%, 40% and 67.9% (P<0.001); COX-2 - 7.7%, 39.3%, 80% and 100% (P<0.001). Stromal VEGF expression was higher than epithelial expression in all CIN grades and was also associated with the lesion grade, while c-fms and COX-2 stromal expression was weak. VEGF expression was statistically correlated to c-fms and COX-2 expression in high-grade CIN (P=0.020 and P=0.027, respectively) and SCC (P=0.015 and P=0.005, respectively). CONCLUSIONS On the basis of our findings, these factors may participate in the development and progression of CIN lesions, with possible interaction of c-fms and COX-2 on VEGF expression, and may be potential molecular targets for studies of cervical cancer prevention and treatment.

Primary papillary serous carcinoma of the peritoneum: CT-pathologic correlation.

We present the CT findings of three cases of primary papillary serous carcinoma of the peritoneum. All patients presented with massive ascites. CT of the abdomen and pelvis showed omental caking in all patients. The parietal peritoneum of the pelvis showed diffuse enhancement with nodular thickening in all patients. No calcification was noted in the omental and parietal peritoneal masses, although psammoma bodies were present microscopically in one case. The ovaries were normal in size but showed a fine enhancing surface nodularity similar to the pelvic peritoneum. The CT findings of primary papillary serous carcinoma of the peritoneum are nonspecific, but this diagnosis should be considered when peritoneal carcinomatosis is seen on CT with normal-sized ovaries in the absence of other primary malignant neoplasms.

Update on the Bethesda System for reporting cervical/vaginal diagnoses.

No public health measure has contributed as much to cancer prevention as the institution of widespread Pap smear screening. There has been abundant epidemiologic evidence, both from North America and Scandinavia [1–8], that mortality from invasive cervical cancer is diminished in screened populations. A more recent study from the Centers for Disease Control has again confirmed decreased mortality from cervical cancer, even when corrected for the prevalence of hysterectomy among those screened [9]. The Pap smear’s empirical success appears to be related to two factors: the accessibility of the cervix for cytologic sampling and the relatively long preinvasive phase of cervical neoplasia, variously known as dysplasia, cervical intraepithelial neoplasia (CIN), and most recently, in the Bethesda System, as squamous intraepithelial lesion (SIL) (see table 1). Abnormalities in epithelial maturation of increasing severity are transmitted to exfoliated cells detected in the Pap smear. This spectrum of epithelial change corresponds to increasing risk of progression to invasive squamous cell carcinoma. Patients whose smears contain abnormal cells are then referred for colposcopic examination, where precancerous lesions can be confirmed by biopsy and obliterated by cryotherapy, laser therapy, or surgical intervention, thus aborting the carcinogenic process within the affected epithelium.

Cytologic changes in cervical smears associated with prolonged use of depot‐medroxyprogesterone acetate

Hormonal effects have always played a significant role in gynecologic cytology. In atrophic and postpartum smears, interpretation may be complicated by large numbers of parabasal cells with high nuclear cytoplasmic ratios and hyperchromatic nuclei that mimic precancerous lesions (squamous intraepithelial lesions, SILs). The authors have observed atrophic and postpartumlike changes in patients receiving depot‐medroxyprogesterone acetate for prolonged periods. These alterations may lead to diagnostic uncertainty or falsely suggest the presence of SIL.

Papilloma of Bartholin's gland duct cyst: First report of a case

A 50-year-old woman underwent excision of a vaginal cyst. Its distal end lay in the submucosal tissue of the posterior lateral aspect of the vulvar vestibule near the orifice of Bartholins gland. The caudal wall of the cyst contained a papilloma with an epithelial lining which consisted of columnar and stratified polygonal cells resembling squamous and transitional epithelium. The histochemical attributes of the papillary epithelium were homologous to those of Bartholins gland. Immunohistochemical studies supported glandular and squamous differentiation. Evolution from a dysontogenetic remnant of Müllerian origin cannot be excluded with certainty, but location and histopathology were consistent with origin from Bartholins gland duct. The presence of mucin and the absence of a smooth muscle investment exclude derivation from Gartners duct. Cysts of Bartholins gland are common, but solid benign tumors are rare. We have been unable to find a report of a papilloma of either vulva or vagina with features similar to those in our patient.

Endocervical neoplasia in long-term users of oral contraceptives: clinical and pathologic observations.

Adenocarcinoma of the cervix has been associated with oral contraceptive use, often prolonged. The clinicopathologic features of seven cases of endocervical neoplasia in long-term combination pill users, all 33 years of age or younger, were reviewed and compared with seven cases in nonusers. Duration of drug use ranged from 4.5 to nine years. Adenocarcinoma in situ was found in all cases either in pure form or associated in invasive adeno- or adenosquamous carcinoma; squamous carcinoma in situ (CIS) was seen in two cases, one of which showed focal microinvasion. Hypersecretory changes were seen in adjacent endocervix in two cases but the morphology of neoplastic lesions was similar to that unassociated with pill use. The possible role of chronic hormonal stimulation in cervical carcinogenesis is discussed in light of these findings and current epidemiologic data.

Computer-assisted immunohistochemical analysis of cervical cancer biomarkers using low-cost and simple software

The study of biomarkers by immunohistochemistry (IHC) for cervical cancer and intraepithelial lesions is a promising field. However, manual interpretation of IHC and reproducibility of the scoring systems can be highly subjective. In this article, we present a novel and simple computer-assisted IHC interpretation method based on cyan-magenta-yellow-black (CMYK) color format, for tissues with diaminobenzidine cytoplasmatic staining counterstained with methyl green. This novel method is more easily interpreted than previous computer-assisted methods based on red-green-blue (RGB) color format and presents a strong correlation with the manual H-score. It is simple, objective, and requires only low-cost software and minimal computer skills. Briefly, a total of 67 microscopic images of cervical carcinoma, normal cervix, and negative controls were analyzed in Corel Photo Paint X3 software in CMYK and RGB color format, and compared with manual H-score IHC assessments. The clearest and best positive correlation with the H-score was obtained using the image in CMYK color format and crude values of magenta color (Spearman correlation coefficient=0.84; agreement of 93.33%, P<0.001). To obtain this value, only 3 steps were necessary: convert the image to CMYK format, select the area of interest for analysis, and open the color histogram tool to visualize the magenta value.

Unique collision of Hodgkin lymphoma and adenosquamous carcinoma in the uterine cervix: Synchronous malignant neoplasms of the cervix

To document the first reported synchronous occurrence of Hodgkin lymphoma and adenosquamous carcinoma involving the female genital tract. Review of cytologic, histologic, and immunohistochemical studies obtained from a 50-year-old, multiparous, postmenopausal, Hispanic female who had a left inguinal mass, bilateral lower extremity pain and numbness, fatigue, anorexia, a 20- to 30-pound weight loss, and a malodorous vaginal discharge at presentation is presented. Cervical squamous cell carcinoma was diagnosed by routine cytologic and histologic analysis. Hodgkin lymphoma subsequently was diagnosed in the inguinal lymph nodes by fine-needle aspiration biopsy and excisional biopsy before the patient underwent hysterectomy. In addition to invasive and in situ adenosquamous carcinoma of the uterine cervix, the hysterectomy specimen also contained previously unsuspected Hodgkin lymphoma. To our knowledge, this is the first reported case of adenosquamous carcinoma and Hodgkin lymphoma synchronously involving the female reproductive tract.