False-negative Papanicolaou tests in women with biopsy-proven invasive endocervical adenocarcinoma/adenocarcinoma in situ: a retrospective analysis with assessment of interobserver agreement.

INTRODUCTION: The objectives of our study were to identify factors contributing to false-negative Papanicolaou (Pap) tests in patients with endocervical adenocarcinoma (EA) or adenocarcinoma in situ (AIS), and to analyze the impact of educational instruction on interobserver agreement in these cases. MATERIALS AND METHODS: False-negative Pap tests from patients with EA/AIS were reviewed by a consensus group and by 12 individual reviewers in 2 rounds, with an educational session on glandular neoplasia in Pap tests conducted between the 2 rounds. RESULTS: Of 79 Pap tests from patients with EA/AIS, 57 (72.2%) were diagnosed as abnormal and 22 (27.8%) as negative. Of the 22 false-negative cases, 10 remained negative on consensus review, with false-negative diagnoses attributed to sampling variance. The other 12 cases were upgraded to epithelial abnormalities (including 8 to glandular lesions). The false-negative diagnoses were attributed to screening variance in 2 cases and interpretive variance in 10 cases. On individual review, abnormal cells were misinterpreted as reactive glandular cells or endometrial cells in 7 of 8 and 5 of 8 cases upgraded to glandular abnormalities, respectively. With education, the proportion of individual reviewers demonstrating at least moderate agreement with the consensus diagnosis (Cohen's kappa >0.4) increased from 33% (4 of 12) to 75% (9 of 12). CONCLUSIONS: Sampling and interpretive variance each accounted for nearly one-half of the false-negative Pap tests, with underclassification as reactive glandular or endometrial cells the main source of the interpretive variances. Educational instruction significantly decreased the interpretive variance and interobserver variability in the diagnosis of glandular abnormalities.

Adaptive Radiation Therapy for Intact Thymoma: An Illustrative Report.

BACKGROUND/AIM: Adaptive radiation therapy (ART) is a technique capable of reducing radiation dose to normal tissue without compromising local control. For potentially resectable thymoma, induction therapy is standard of care. Because large disease volume is common in this context, ART has been suggested to reduce toxicity from induction chemoradiation. This has not been previously illustrated in the literature. CASE REPORT: A 38-year-old man with initially unresectable thymoma was treated with induction chemoradiation including cisplatin and etoposide. He received 45 Gy in 25 fractions and ART was utilized to shrink the radiotherapy field for the final 10 fractions. RESULTS: Thymectomy showed Masaoka stage III disease with negative margins. He experienced no treatment-related toxicity and has no evidence of disease 8 years after diagnosis. CONCLUSION: Induction chemoradiotherapy with ART appears to be feasible, safe, and efficacious for locally advanced intact thymoma.

Ovarian Low-grade Serous Carcinoma: A Clinicopathologic Study of 33 Cases With Primary Surgery Performed at a Single Institution.

Ovarian low-grade serous carcinoma (LGSC) is an entity with distinct pathologic and clinical features. The number of studies on this type of tumor is limited. In this article, we present our experience with 33 cases of ovarian LGSC with primary surgical treatment at our institution. For comparison, a cohort of ovarian high-grade serous carcinoma (HGSC) was also studied. Clinical information was obtained from the patients' charts or from the treating physicians. Hematoxylin and eosin slides were reviewed of 28 available LGSCs, and the following parameters were recorded: presence/absence of a serous borderline tumor (SBT), presence/absence of micropapillary/cribriform pattern (MP/CP), architectural pattern in the invasive component, and presence/absence of desmoplasia or fibrosis. The incidence of ovarian LGSC was 4.7%. LGSC patients ranged in age from 19 to 79 years (mean, 52 y), with 21.2% younger than 40 years. HGSC patients ranged in age from 38 to 90 years (mean, 62 y), with 1.6% younger than 40 years. LGSCs were staged as follows: stage I (2), stage III (23), and stage IV (8). Twenty-eight of 33 LGSC cases had concurrent SBT, with this component accounting for >50% of the neoplasm in 15 cases. In addition, MP/CP was noted in 19 cases. Invasion patterns included micropapillae (93%), cribriform nests (74%), elongated papillae (26%), glandular (44.4%), medium-sized papillae (33.3%), solid nests (22.2%), macropapillae (19%), and single cells (19%). In addition, desmoplasia (44.4%) and fibrosis (37%) were noted. Follow-up data ranging from 13 to 195 months (median 61.2 mo) were available on 30/33 LGSC patients: 18 (60%) were dead of disease; 1 (3.3%) was dead of other cause; 5 (16.7%) were alive with disease; and 6 (20%) had no evidence of disease. Follow-up data from 1 to 169 months (median 48 mo) were available on 185 HGSC patients: 132 (71.4%) were dead of disease; 3 (1.6%) were dead of other cause; 21 (11.4%) were alive with disease; and 29 (15.7%) had no evidence of disease. Ovarian LGSC is rare with a predilection for younger patients relative to HGSC. Most LGSC cases are associated with SBT with an MP/CP, and their invasive component usually contains a micropapillary pattern. Most patients with ovarian LGSC present with advanced-stage disease and have a short-term survival advantage over patients with HGSC (estimated 5 y survival: 62.3% vs. 43.9%). However, over a prolonged period of time, this survival advantage decreases (estimated 10 y survival: 21.2% vs. 22.7%).

Defective DNA Mismatch Repair Influences Expression of Endometrial Carcinoma Biomarkers.

Endometrial endometrioid carcinomas are related to estrogen excess and express estrogen and progesterone receptors. However, hormone receptor expression can be variable from tumor to tumor, and this variability is not always explained by differences in tumor grade. Variable expression of other biomarkers that may be used in the diagnostic work-up of endometrial cancer has also been noted. We hypothesized that mismatch repair (MMR) defects may contribute to this variability. A total of 411 unselected endometrial carcinomas were evaluated for immunohistochemical expression of DNA MMR proteins and MLH1 methylation. Loss of immunohistochemical expression of MLH1, MSH2, MSH6, or PMS2 was defined as MMR deficient; positive expression was defined as MMR intact. A case-control cohort of 80 Grade 2 endometrioid carcinomas was selected from this set (40 MMR deficient, 40 MMR intact). Cases were matched for histotype, grade, and age. Estrogen receptor, progesterone receptor, CK7(+), CK20, and Pax-8 immunohistochemistry was evaluated. The median percentage of CK7 tumor cells was significantly lower in the MMR deficient group compared with the MMR intact group. The mean percentage of tumor cells exhibiting estrogen receptor expression was similar in both the MMR-deficient and MMR intact groups. However, there was greater variability in the MMR-deficient group. Our study shows that MMR defects influence the expression of clinically important biomarkers for endometrioid-type endometrial carcinoma as decreased cytokeratin 7 expression is more commonly associated with MMR deficiency.

The Utility of Core Needle Biopsy and Fine-Needle Aspiration in the Workup of Tumors of Suspected Müllerian Origin.

OBJECTIVES: Core needle biopsy (CNB) and fine-needle aspiration (FNA) for tumors of suspected Müllerian origin may prevent unnecessary laparotomies and allow patients the benefit of neoadjuvant chemotherapy. An assessment of the utility and limitations of CNB/FNA, with incorporation of current immunohistochemistry, is needed. STUDY DESIGN: Two hundred nineteen female patients with CNB/FNA of the omentum, pelvis, abdomen, adnexa, ovary, uterus, and fallopian tube were identified. From these, 30 consecutive CNB/FNA with corresponding surgical resection were reviewed to assess diagnostic agreement and identify potential diagnostic pitfalls. RESULTS: The most frequent diagnosis overall was adenocarcinoma (96/219; 43.8%), most commonly adenocarcinoma of gynecologic origin (65/219; 30%). Nondiagnostic or unsatisfactory material was present in a minority of cases (10/219; 5%). In the 30 CNB/FNA cases examined for diagnostic agreement with surgical resection, 24 (80%) had exact or essential agreement with the final diagnosis. Of the 23 cases that were positive and/or suspicious on cytology, 18 (78%) had neoadjuvant chemotherapy or radiation treatment prior to surgical resection. CONCLUSIONS: The majority of CNB/FNA for tumors of suspected Müllerian origin are diagnostic, correlate with the surgical resection, and contribute to management. A standard diagnostic algorithm is suggested.

De novo large cell neuroendocrine carcinoma of the prostate gland with pelvic lymph node metastasis: a case report with review of literature.

Neuroendocrine (NE) differentiation in prostate carcinomas can be seen in two settings: as a focal finding in conventional acinar adenocarcinoma, identifiable by immunohistochemical staining, or as a primary NE tumor of the prostate gland, such as carcinoid, small cell carcinoma, or large cell NE carcinoma. Of particular interest is the large cell NE carcinoma, which had been previously reported in isolated cases or in limited case series. In this report, we describe a case of a large cell NE carcinoma diagnosed in a 48-year-old man who presented with difficulty in voiding and urine retention. A cystoscopy revealed an enlarged, elongated prostate with an intra-urethral obstructing mass in the prostatic urethra. Subsequently, a transurethral resection of prostate (TURP) was performed at an outside hospital under the clinical diagnosis of benign prostatic hyperplasia (BPH). Microscopic examination of the TURP specimen revealed several foci of low-grade transitional-zone-type adenocarcinoma corresponding to Gleason score 5 (3 + 2), and a focus of high-grade large cell NE carcinoma. Concurrent x-ray computed tomography scans of the chest, abdomen, and pelvis demonstrated an enlarged left pelvic lymph node, which was biopsied and the patient was diagnosed with metastatic large cell NE carcinoma. He subsequently underwent 8 cycles of neoadjuvant chemotherapy with Lupron, a laparoscopic robotic-assisted radical retropubic prostatectomy, and pelvic lymphadenectomy. He died of widely metastatic prostatic carcinoma with leptomeningeal metastases 13 months after radical prostatectomy. Here, we present a rare case of large cell NE carcinoma with a review of the published literature.