Cindy McGrath

Hypoxia-Inducible Erythropoietin Signaling in Squamous Dysplasia and Squamous Cell Carcinoma of the Uterine Cervix and Its Potential Role in Cervical Carcinogenesis and Tumor Progression

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Placental infection with human papillomavirus is associated with spontaneous preterm delivery

BACKGROUND We sought to determine if human papillomavirus (HPV) infection of extravillous trophoblast cells reduces cell invasion and if placental infection is associated with adverse reproductive outcomes attributed to placental dysfunction. METHODS We conducted apoptosis and invasion assays using extravillous trophoblast (HTR-8/SVneo) cells that were transfected with a plasmid (pAT-HPV-16) containing the entire HPV-16 genome. In order to associate HPV infection with reproductive outcomes, we conducted a case-control study to detect HPV DNA in the extravillous trophoblast region of placentas from cases of spontaneous preterm delivery, severe pre-eclampsia requiring delivery at <37 weeks and controls who delivered at term. RESULTS Rates of apoptosis were 3- to 6-fold greater in transfected cells than in non-transfected cells or cells transfected with an empty plasmid. Invasion of transfected cells through extracellular matrices was 25-58% lower than that of the controls. HPV was detected more frequently in placentas from spontaneous preterm deliveries than in placentas from controls (P = 0.03). Identification of HPV in placentas from cases of pre-eclampsia was not significantly different to controls. CONCLUSIONS HPV infection of extravillous trophoblast induces cell death and may reduce placental invasion into the uterine wall. Thus, HPV infection may cause placental dysfunction and is associated with adverse pregnancy outcomes, including spontaneous preterm delivery.

Lobectomy with tangential pulmonary artery resection without regard to pulmonary function

BACKGROUND Non-small cell carcinoma of the lung invading the pulmonary artery (PA) has traditionally been treated by pneumonectomy. Although PA resection and reconstruction (PAR) has begun to gain acceptance, previous series of PAR by the simplest technique of tangential excision and primary repair have been unfavorable. We have maintained a policy of performing PAR preferentially whenever anatomically feasible, and usually this has been possible by tangential excision and primary repair. This study sought to determine if this approach is sound. METHODS Retrospective clinical and pathologic review. RESULTS Thirty-three PARs were performed from 1992 to 1999. The patients, followed 6 to 65 months (mean 25), were aged 36 to 80 years (mean 61), and their tumors were pathologic stage IB (n = 7), IIB (n = 13), IIIA (n = 9), and IIIB (n = 4). The mean preoperative forced expiratory volume in 1 second was 70% predicted. The procedures included 14 bronchial sleeve lobectomies with PAR and 19 simple lobectomies with PAR. The PARs were performed without heparinization and included 19 tangential excisions with primary closure, 11 larger tangential excisions with pericardial patch closure, and 3 sleeve resections. There were no operative deaths and 2 (6.1%) early major complications, all unrelated to the PAR. Thirteen patients (39%) had early minor complications. Four-year Kaplan-Meier survival was 48.3% for stages I/II and 45% for stage III. Ipsilateral, central, intrathoracic recurrence occurred in 3 patients (9.1%). CONCLUSIONS These data are not dramatically different from those reported for standard resections. Although the numbers are small, the results suggest that lobectomy with PAR by tangential excision is an acceptable alternative to pneumonectomy whenever anatomically possible.

Using “residual” FNA rinse and body fluid specimens for next‐generation sequencing: An institutional experience

Tissue specimens are typically considered optimal for molecular testing; however, in the current era of personalized medicine, cytopathology specimens are increasingly recognized as potential sources for molecular testing. This is often accomplished by using cell block specimens and/or fine‐needle aspiration (FNA) smear preparations. In this study, the authors investigated the feasibility, performance, and quality of “residual” FNA rinse and body effusion fluids used for next‐generation sequencing (NGS).

Evaluation of mild‐to‐moderate dysplasia on cervical‐endocervical (Pap) smear: A subgroup of patients who bridge LSIL and HSIL

The Bethesda System recommends Pap smear diagnosis to be based on the most abnormal cells present, regardless of number. Our reporting system includes a diagnostic category of mild‐to‐moderate dysplasia (D1‐2), defined as cases with only a few moderately dysplastic cells. We evaluated the validity of a D1‐2 diagnostic category by reevaluation of 58 cases with subsequent follow‐up (up to 24 months). On biopsy and/or Pap smear follow‐up, 24 cases (41%) showed LSIL and 34 cases (59%) showed HSIL. Index smears from these cases were examined by two cytopathologists blinded to patient follow‐up for the following morphologic features: volumes (scale 1–4) of LSIL, HSIL, and dyskeratosis, HSIL as single cells or syncytial fragments, and acute inflammation. None of the morphologic features evaluated were significantly different between the LSIL and HSIL follow‐up groups based on univariate and multivariate logistic regression analysis. The diagnosis of D1‐2 on Pap smear is a valid diagnostic category that defines a subgroup of patients with both LSIL and HSIL follow‐up, which cannot be reliably predicted based on morphology alone. Diagn. Cytopathol. 2000;23:245–248.

Vaginal intraepithelial neoplasia (VAIN) after radiation therapy for gynecologic malignancies: A clinically recalcitrant entity

OBJECTIVES Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institutions experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. METHODS A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). RESULTS Mean follow-up after initial diagnosis of VAIN was 37.6 months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3 months in cases and 15.3 months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3 month to 12 month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. CONCLUSIONS Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario.

Duodenal carcinoid tumor: report of a case diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy with immunocytochemical correlation.

Fine‐needle aspiration biopsy is a reliable and accurate method for the endoscopic diagnosis of gastrointestinal malignancies and it is particularly well suited for evaluation of submucosal lesions. We report the cytopathologic findings of a case of malignant carcinoid tumor of a 44‐year‐old male who presented with melena and a nonhealing duodenal ulcer. Endoscopic ultrasound examination revealed a submucosal lesion in the pyloric region. Fine‐needle aspiration revealed abundant cellularity with tumor cells arranged in sheets and loose groups and dispersed single cells in a clean background. Papillary fragments, capillaries cuffed by tumor cells, and rosette formation were also noted. The cells were moderate in size, round to oval, with a small subpopulation of spindle‐shaped cells. The nuclei were uniform, round to oval, with smooth nuclear borders. The chromatin pattern was finely granular with a salt‐and‐pepper appearance. The cytoplasm of the cells was small to moderate in amount, pale, and showed fine granularity. The differential diagnosis included a neuroendocrine neoplasm vs. an epithelioid gastrointestinal stromal tumor. The tumor cells were focally positive for chromogranin and negative for CD34, supporting the diagnosis of a neuroendocrine neoplasm. The differential diagnosis of primary gastrointestinal carcinoid tumors from gastrointestinal stromal tumors can be very difficult in cytologic material. In cases when diagnostic material is scant, or only present on one smear, the use of smear division and cell transfer in order to perform immunocytochemical stains may be of considerable value to confirm the neuroendocrine nature of the neoplasms. Diagn. Cytopathol. 2000;23:183–186.

Thyroid Nodule Fine-Needle Aspiration

Thyroid nodules are a common clinical problem and are noted much more commonly on imaging examinations than are apparent by palpation. Fine-needle aspiration biopsy (FNA), which yields a cytology specimen for analysis, is the standard test to determine whether surgical removal of a detected nodule is recommended. This article will review the current guidelines for recommending FNA of thyroid nodules, the technique and risk of the procedure, and the implications for patient care based on FNA results. FNA has an essential role in the evaluation of patients with thyroid nodules to reduce the rate of unnecessary thyroid surgery for patients with benign nodules and triage patients with thyroid cancer to appropriate surgery. Before the routine use of FNA, approximately 14% of resected thyroid nodules were malignant, whereas with the current widespread use of thyroid nodule FNA, >50% of resected thyroid nodules are malignant. Historically, thyroid nodules were identified by physical examination of the neck, with a prevalence of approximately 5%-10% of adults in the United States, and these patients underwent palpation-guided FNA in the physicians office. In recent years, the increased use of sonography to examine the thyroid as well as cross-sectional imaging of the neck by computed tomography and magnetic resonance imaging has resulted in the detection of many nonpalpable nodules. In older adults, thyroid nodules may be detected in >67% of people screened by sonography. Fortunately, the vast majority of nodules are benign, but when they are discovered, an assessment regarding the need to exclude malignancy using FNA must be performed.

Papillary thyroid cancer arising in struma ovarii

Malignant struma ovarii is a rare clinical entity that poses a therapeutic challenge, as there is no ‘gold standard’ of care. We aimed to develop evaluation and treatment guidelines by reviewing presentation and outcomes of the available literature. We present a 60-year-old female with papillary thyroid carcinoma arising in a mature teratoma, and our multidisciplinary approach to care and follow-up. We examined 59 cases for characteristics, including rates of metastasis and recurrence, and response to surgical and adjuvant treatment. We found higher rates of metastasis and recurrence than traditionally reported, and found no recurrence in patients treated with oophorectomy, thyroidectomy, and I-131 radioablation. A multimodal approach to the treatment of malignant struma ovarii may improve survival and decrease risk of recurrence.

AGA White Paper: Optimizing Endoscopic Ultrasound–Guided Tissue Acquisition and Future Directions

*Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California; Department of Pathology and Laboratory Medicine, Perelman School of Medicine and University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; kDepartment of Pathology and Cell Biology, Columbia University, New York, New York; Arizona Center for Digestive Health, Gilbert, Arizona; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; **Division of Gastroenterology, Perelman School of Medicine and the University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and Division of Gastroenterology and Hepatology, Ochsner Medical Center, New Orleans, Louisiana