Combined Hepatocellular Neuroendocrine Carcinoma: A Rare Tumor.

Neuroendocrine tumors originate from neuroendocrine cells primarily located in the gastrointestinal tract. These tumors often metastasize to the liver. Primary hepatic neuroendocrine carcinomas are uncommon, and combined hepatocellular neuroendocrine carcinomas are exceedingly rare. There is a lack of data on the management of these rare tumors. Most cases have very poor prognosis secondary to aggressive behavior of the neuroendocrine tumor component. It is important for clinicians to be aware of this rare carcinoma to allow for early diagnosis and optimize potential treatment options.

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.

Mycobacterium tuberculosis diagnosed promptly by bronchial brushing cytology in an immunocompetent patient.

Respiratory cytology plays an important role in the diagnosis of lower respiratory tract infection. The timely diagnosis of pulmonary tuberculosis (TB) can be very challenging due to the nonspecific cytomorphologic features and limited number of organisms, especially in the immunocompetent patients. Here, we reported a case of TB diagnosed promptly by bronchial brushing cytology in a 51-year-old immunocompetent patient. She presented with a 4 cm fungating lesion involving right lower lobe of the lung and mediastinal lymphadenopathy with an initial concern for malignancy. Bronchial brushing showed scattered acute inflammatory cells in the background of necrosis. A cell block was prepared and acid-fast bacilli (AFB)-positive organisms were identified. Subsequent polymerase chain reaction (PCR) performed on the sputum detected Mycobacterium tuberculosis. This case highlights the importance of recognizing the cytomorphology of TB from a bronchial brushing specimen; and also emphasizes the potential utility of the cell block from respiratory cytology in the diagnosis of TB.

Molecular Modifiers of Hormone Receptor Action: Decreased Androgen Receptor Expression in Mismatch Repair Deficient Endometrial Endometrioid Adenocarcinoma.

Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.

Identification of a subset of microsatellite-stable endometrial carcinoma with high PD-L1 and CD8+ lymphocytes.

Immune checkpoint blockade has emerged as an effective therapeutic strategy for patients with advanced cancer. Identification of biomarkers associated with treatment efficacy will help to select patients more likely to respond to this approach. High levels of microsatellite instability, tumor expression of PD-L1, high tumor mutation burden, and increased tumor-infiltrating lymphocytes have all been associated with response to checkpoint inhibitor blockade. The purpose of this study was to determine if a subset of microsatellite-stable endometrioid endometrial carcinomas have higher immune cell infiltrates and/or expression of PD-L1. PD-L1 expression and characterization of immune cell infiltrates were analyzed in 132 microsatellite stable, FIGO grade 2 endometrioid carcinomas. PD-L1 was positive in 48% (63/132) of the tumors. Tumor cell expression of PD-L1 was significantly associated with lymphatic/vascular invasion and deep myometrial invasion. PD-L1 expression was especially prominent at the invasive front and in foci of tumor-associated squamous metaplasia. Twenty-one cases (16% of the total) with more diffuse and/or especially strong PD-L1 expression were identified. This PD-L1 high subset was associated with significantly higher numbers of tumor-associated CD3+ and CD8+ lymphocytes. Only one tumor in the PD-L1 high subset harbored a POLE mutation. PTEN immunohistochemical loss, a common event in endometrioid-type endometrial carcinoma and associated with local immune suppression in melanoma, was not associated with PD-L1 expression or lymphocyte/macrophage infiltration of the tumor. These results suggest that a subset of microsatellite-stable endometrial cancers has higher expression of PD-L1 and increased tumor-associated CD3+ and CD8+ lymphocytes, characteristics more commonly associated with endometrial cancers with high levels of microsatellite instability. These results suggest that screening strategies to select only microsatellite instability-high advanced endometrial cancers for checkpoint inhibitor therapy might exclude patients who could potentially benefit from this therapeutic approach.

Next-Generation Sequencing of Matched Primary and Metastatic Rectal Adenocarcinomas Demonstrates Minimal Mutation Gain and Concordance to Colonic Adenocarcinomas.

CONTEXT: -Colorectal carcinoma is the third most common cause of cancer death in males and females in the United States. Rectal adenocarcinoma can have distinct therapeutic and surgical management from colonic adenocarcinoma owing to its location and anatomic considerations. OBJECTIVE: -To determine the oncologic driver mutations and better understand the molecular pathogenesis of rectal adenocarcinoma in relation to colon adenocarcinoma. DESIGN: -Next-generation sequencing was performed on 20 cases of primary rectal adenocarcinoma with a paired lymph node or solid organ metastasis by using an amplicon-based assay of more than 2800 Catalogue of Somatic Mutations in Cancer (COSMIC)-identified somatic mutations. RESULTS: -Next-generation sequencing data were obtained on both the primary tumor and metastasis from 16 patients. Most rectal adenocarcinoma cases demonstrated identical mutations in the primary tumor and metastasis (13 of 16, 81%). The mutations identified, listed in order of frequency, included TP53, KRAS, APC, FBXW7, GNAS, FGFR3, BRAF, NRAS, PIK3CA, and SMAD4. CONCLUSIONS: -The somatic mutations identified in our rectal adenocarcinoma cohort showed a strong correlation to those previously characterized in colonic adenocarcinoma. In addition, most rectal adenocarcinomas harbored identical somatic mutations in both the primary tumor and metastasis. These findings demonstrate evidence that rectal adenocarcinoma follows a similar molecular pathogenesis as colonic adenocarcinoma and that sampling either the primary or metastatic lesion is valid for initial evaluation of somatic mutations and selection of possible targeted therapy.

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.

PAX2 and PAX8: useful markers for metastatic effusions.

OBJECTIVE: It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. STUDY DESIGN: PAX2 and PAX8 immunohistochemical staining was performed on cell blocks of 89 pleural, pericardial and peritoneal effusions with benign diagnoses (18 cases), or secondary to renal cell carcinoma (RCC; 9 cases), müllerian carcinoma (21 cases) or non-müllerian carcinoma (41 cases). RESULTS: PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of müllerian carcinomas, and 2% (1/41) of non-müllerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of müllerian carcinomas, and 5% (2/41) of non-müllerian carcinomas. PAX2 was 35% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. CONCLUSIONS: PAX8 is more sensitive than PAX2 for metastatic effusions from müllerian carcinomas (100 vs. 35%), while also having a higher intensity of staining than PAX2. However, PAX2 and PAX8 are both highly sensitive and specific for RCCs. PAX2 and PAX8 are valuable diagnostic markers for metastatic müllerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of müllerian origin.

Renal cell carcinoma: Evolving and emerging subtypes.

Our knowledge of renal cell carcinoma (RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC.

Interstitial cystitis: another IgG4-related inflammatory disease?

Interstitial cystitis (IC) is a disease of undetermined etiology and pathogenesis. Inflammation is thought to play a key role in many patients, characteristically with an increase in mast cells within the detrusor muscle of the bladder. We observed that some patients with IC had prominent plasma cells in bladder tissue, which elicited our interest in their possible pathogenic role in patients with IC. A total of 44 cases of IC were collected, including 42 bladder biopsies and 2 cystectomies. Patient age ranged from 18 to 92 years (average age of 49.5 years) and included 7 male and 37 female patients. The histology and immunostains for IgG, IgG4 and tryptase were examined, and the results were correlated with clinical and cystoscopic findings. Four cases showed a significant increase in IgG4-positive plasma cells, with greater than 30 IgG4 plasma cells per high-power field and an IgG4/IgG ratio greater than 0.5. In addition, statistically significant differences were found between IC with IgG4-positive plasma cells vs IgG4-negative cases. The IgG4-positive patients were of older age and had increased severe inflammation and decreased bladder capacity as compared with the IgG4-negative patients. We propose that a subset of patients with IC may have an IgG4-related disease, and further study including serum IgG4 measurement is required to better define this relationship.