Synovial Sarcoma of the Gastrointestinal Tract.

We report the clinicopathologic and immunohistochemical features of 18 cases of confirmed primary synovial sarcoma of the gastrointestinal tract. The neoplasms arose in 10 women and 8 men ranging in age from 23 to 81 years (mean: 50; median: 57.5 years). The tumors for which size was known ranged from 1.8 to 15.0 cm (mean: 5.2; median: 5.1 cm). Microscopically, 14 synovial sarcomas were of the monophasic type, 2 were biphasic, and 2 were poorly differentiated. Immunohistochemical analysis of 4 cases showed strong, diffuse staining for SS18::SSX (4/4 cases). Pancytokeratin and EMA immunohistochemistry were performed on 13 and 9 tumors, respectively, and each showed patchy-to-diffuse staining. By reverse-transcription PCR, 3 cases were positive for the SS18::SSX1, and 2 cases were positive for the SS18::SSX2 gene fusion. Six cases contained an SS18 gene rearrangement by fluorescence in situ hybridization, and next-generation sequencing identified an SS18::SSX2 gene fusion in one case. Clinical follow-up information was available for 9 patients (4 months to 4.6 years; mean, 2.8 y; median: 29 months), and one patient had a recent diagnosis. Three patients died of disease within 41 to 72 months (mean, 56 months) of their diagnosis. Five patients were alive without evidence of disease 4 to 52 months (mean, 17.6 months) after surgery; of whom 1 of the patients received additional chemotherapy treatment after surgery because of recurrence of the disease. A single patient was alive with intraabdominal recurrence 13 months after surgery. We conclude that synovial sarcoma of the gastrointestinal tract is an aggressive tumor, similar to its soft tissue counterpart, with adverse patient outcomes. It is important to distinguish it from morphologically similar gastrointestinal tract lesions that may have different treatment regimens and prognoses.

Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis.

Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis.

The Morphologic Spectrum of Gastric Type 1 Enterochromaffin-Like Cell Neuroendocrine Tumors.

Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.

NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1.

BACKGROUND: H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models. METHODS: To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays. RESULTS: Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models. CONCLUSION: Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.

Sucrase-Isomaltase Deficiency as a Potential Masquerader in Irritable Bowel Syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) frequently have meal-related symptoms and can recognize specific trigger foods. Lactose intolerance is a well-established carbohydrate malabsorption syndrome that causes symptoms similar to IBS such as bloating, abdominal pain, and diarrhea. However, the prevalence of sucrase-isomaltase deficiency (SID) in this population is poorly defined. SID is a condition in which sucrase-isomaltase, an enzyme produced by brush border of small intestine to metabolize sucrose, is deficient. Just like lactase deficiency, SID causes symptoms of maldigestion syndromes including abdominal pain, bloating, gas, and diarrhea. In this study, we aim to determine the prevalence of SID in patients with presumed IBS-D/M and characterize its clinical presentation. METHODS: Patients with a presumed diagnosis of IBS-D/M based on symptoms of abdominal pain, diarrhea, and/or bloating who underwent esophagogastroduodenoscopy with duodenal biopsies and testing for disaccharidase deficiency were included. Patients with a history of inflammatory bowel disease, gastrointestinal malignancy, or celiac disease were excluded. Odds ratio was calculated for abdominal pain, diarrhea, and bloating in patients with versus without SID. RESULTS: A total of 31 patients with clinical suspicion for IBS-D/M were included with a median age of 46 years (IQR 30.5-60) and with 61% females. SID was present in 35% of patients. Among patients with SID, 63.6% had diarrhea, 45.4% had abdominal pain, and 36.4% had bloating. Patients with SID were less likely than controls to have abdominal pain (OR 0.16, 95% CI 0.03-0.81, p = 0.04) although no difference in diarrhea or bloating was found. Only two patients with SID underwent sucrose breath testing of which only one had a positive result. However, this patient also had a positive glucose breath test and may have had small intestinal bacterial overgrowth as a confounder. CONCLUSION: SID was found in 35% of patients with presumed IBS-D/M and should be considered in the differential diagnosis of patients presenting with abdominal pain, diarrhea, or bloating. Further studies should better characterize the clinical features of SID and investigate the effects of dietary modification in this group of patients.

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.

BACKGROUND: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-ß levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-ß could be a predictive biomarker for response to pembrolizumab.

The immune system and gastrointestinal stromal tumor: a wealth of opportunities.

PURPOSE OF REVIEW: This article reviews the current literature on tumor-infiltrating immune cells in gastrointestinal stromal tumor (GIST), and the current status and prospects of effective immunotherapeutic strategies. RECENT FINDINGS: Tumor-infiltrating immune cells populate the microenvironment of GISTs; the most numerous are tumor-associated macrophages (TAMs) and CD3 T cells. TAMs have not been shown to have a relationship with the biological behavior of GISTs; however, the number of CD3 T cells correlates with better outcomes. The prognostic significance of tumor-infiltrating neutrophils, natural killer cells, CD4 T cells, CD8 T cells, and Treg cells remains unknown.Imatinib mesylate achieves a clinical response in 80% of patients with GIST. Its antitumor mechanism is partially immune mediated. The combination of imatinib and interferon-α has been shown to be effective against GIST - it eradicates tumor cells including those that are drug resistant. Preclinical trials including cytotoxic T lymphocyte-associated antigen 4 blockade, anti-KIT antibody, and the generation of designer T cells have shown promising therapeutic effect in animal models of GIST. SUMMARY: GIST contains many tumor-infiltrating immune cells and should be susceptible to immunotherapy; early clinical and preclinical trials have shown promising results that should lead to new investigations and effective forms of direct and synergistic therapies.

Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia.

BACKGROUND: Although hyperfiltration and albuminuria are common pathological conditions, kidney injury (KI) biomarkers have been seldom studied in individuals with sickle cell anemia (SCA). METHODS: We undertook a cross-sectional assessment of urine KI biomarkers in children and adults with SCA with and without albuminuria and a normal estimated glomerular filtration rate (eGFR). Albumin, KI molecule 1 (KIM-1), N-acetyl-ß-D-glucosaminidase (NAG), endothelin-1 and transforming growth factor-ß1 (TGF-ß1) were measured. Assays were normalized by urine creatinine. Urine intracellular hemosiderin and serum lactate dehydrogenase (LDH) were assessed as markers of hemolysis. Albuminuria was associated to the biomarkers by Pearson and Spearman correlation coefficients. Differences between the albuminuria (yes, no) groups were assessed by the t test. RESULTS: Nineteen patients with albuminuria (mean urine albumin/creatinine 527.14 ± 1070 mg/g, range 38.3--190 mg/g) and 19 patients without albuminuria (mean urine albumin/creatinine 15.93 ± 5.17 mg/g, range 7.9-28.4 mg/g) were studied. The age range for the whole group was 11-48 years, and 47 % were males. Patients with albuminuria were older, had lower hematocrit, were more likely to test positive for urine hemosiderin and had a higher KIM-1 (P = 0.0035) and NAG/ creatinine ratios (P = 0.0062). Urine hemosiderin strongly correlated to a higher LDH level (P < 0.001). CONCLUSIONS: Despite a normal or increased eGFR, KI biomarkers were detected in the urine of individuals with SCA. NAG, KIM-1 and urine hemosiderin correlated with the presence of albuminuria.

Don't SUMP it! Utility of PLAG1 immunocytochemistry in basaloid SUMP subcategory.

BACKGROUND: Basaloid salivary gland neoplasm of uncertain malignant potential (B-SUMP) is an indeterminate diagnostic subcategory, with pleomorphic adenoma (PA) representing the most common benign neoplasm. Pleomorphic adenoma gene 1 (PLAG1) staining is frequently seen in PAs and could aid in distinguishing them from other basaloid neoplasms. The authors evaluated the utility of PLAG1 immunocytochemistry (ICC) in differentiating PAs from other basaloid neoplasms in smears and liquid-based cytology (LBC) specimens. METHODS: In total, 45 B-SUMP cytology aspirates and corresponding surgical excision specimens were identified. PLAG1 immunostaining was performed in all aspirates and surgical excision specimens and was scored as positive (strong/diffuse), equivocal (focal/weak), or negative. RESULTS: PLAG1 ICC was performed directly on 38 smears and seven LBC specimens. PLAG1 was positive in 29 of 45 cases (64%), whereas six of 45 (13%) were equivocal, and 10 of 45 (22%) were negative. PLAG1-positive aspirates included 26 (90%) PAs, two (7%) basal cell adenomas (BCAs), and one (3%) carcinoma ex-PA. PLAG1-equivocal aspirates included four (67%) PAs and two (33%) BCAs, whereas negative aspirates included five (50%) BCAs, four (40%) adenoid cystic carcinomas, and one (10%) metastatic adenosquamous carcinoma. The sensitivity, specificity, positive, and negative predictive values were 87%, 86%, 93%, and 75%, respectively. Diagnostic accuracy was 87%. CONCLUSIONS: PLAG1 ICC is useful when positive (strong/diffuse) and can be reliably performed on smears and LBC specimens. PLAG1 was positive in most PAs and in a small subset of BCAs. Therefore, in the absence of atypical cytologic features, PLAG1-positive tumors could be diagnosed as benign, with a note favoring PA versus BCA. In contrast, PLAG1-negative/equivocal tumors should remain in the B-SUMP category.

Atypia of undetermined significance and ThyroSeq v3-positive call rates as quality control metrics for cytology laboratory performance.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. METHODS: A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. RESULTS: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. CONCLUSIONS: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology.

Atherosclerosis within the non-neoplastic margin of partial nephrectomy specimens: implications for medical management.

PURPOSE: To describe the frequency and severity of atherosclerosis contained within the non-neoplastic tissue of partial nephrectomy (PN) specimens. METHODS: Archived open PN specimens were evaluated for histological evidence of atherosclerosis. Clinically significant atherosclerosis was defined as arterial luminal narrowing of >25% due to fibrointimal thickening. Histological findings were correlated with clinical data including history of major medical comorbidities and preoperative statin use. RESULTS: The study cohort was comprised of 114 patients (71 men and 43 women). The mean age at the time of surgery was 59.3 years, and 69 (60.5%) patients had a history of at least one major medical comorbidity including hypertension (54.5%), diabetes (16.7%) and coronary artery disease (12.3%). Clinically significant atherosclerosis was observed in 29 (25.4%) patients. These individuals were older (p = 0.001), and three times more likely to have greater than one major medical comorbidity (p = 0.002). In addition, only 17 (58.6%) were prescribed a statin at the time of surgery. CONCLUSIONS: Atherosclerosis is frequently observed in the non-neoplastic tissue of PN specimens. Patients found to have atherosclerosis can potentially benefit from intensive lifestyle modification and medical therapy with lipid-lowering medications. These measures would likely have the greatest clinical impact on those patients without an existing history of major medical comorbidities.

Pathologic evaluation of non-neoplastic renal parenchyma in partial nephrectomy specimens.

PURPOSE: This study aimed to identify non-neoplastic pathologic changes in partial nephrectomy specimens of patients without a known history of medical comorbidities. Routine analysis of this tissue may allow the clinician to identify subclinical renal disease. METHODS: We retrospectively reviewed our database of patients who underwent open partial nephrectomy for a small renal mass. Non-neoplastic tissue of partial nephrectomy specimens of patients without a known history of chronic kidney disease, diabetes mellitus, hypertension, or coronary artery disease was evaluated for glomerular, interstitial, and vascular pathologic changes. RESULTS: A rim of non-neoplastic tissue was adequate for pathologic evaluation in 91.8% of specimens. A total of 45 patients were studied with a median age of 52.0 years. Atherosclerosis was the most commonly identified pathologic finding in 9 (20%) patients, followed by mesangial expansion and interstitial fibrosis, each found in 8 (17.8%) patients. Linear regression found interstitial fibrosis to be the only pathologic lesion associated with preoperative serum creatinine (coefficient = 0.697, P = 0.001). Male gender was also associated with a higher preoperative creatinine (coefficient = 0.270, P = 0.034). Postoperative serum creatinine was not associated with any of the examined lesions. CONCLUSIONS: Current surgical techniques provide adequate non-neoplastic tissue for pathologic evaluation. We observed a striking degree of pathologic disease in patients without a known history of medical comorbidities. Routine inspection of the non-neoplastic parenchyma of partial nephrectomy specimens should be performed as it can alert the clinician to presence subclinical renal disease allowing for medical intervention.

An immunohistochemical panel to distinguish ovarian from uterine serous papillary carcinomas.

Serous papillary carcinomas (SPCs) share a similar morphology regardless of whether they originate from the ovary or the uterus. Identification of the site of origin of the tumor can be a challenging and a diagnostic dilemma, particularly, in the setting of a pelvic mass or peritoneal carcinomatosis. Recognition of the site of origin influences the staging, management, and prognosis of these malignancies. The purpose of this study is to identify a panel of markers to distinguish the ovarian serous papillary carcinomas (OSPC) from the uterine serous papillary carcinomas (USPC). Formalin-fixed, paraffin-embedded archival tissue from 46 cases of SPCs (33 uterine and 13 ovarian) were stained using antibodies for estrogen receptor (ER), WT1, insulin-like growth factor-II mRNA-binding protein 3 (IMP3), p53, and p16. The OSPC expressed ER (92%), WT1 (100%), IMP3 (92%), p53 (92%), and p16 (92%). The USPCs expressed ER (30%), WT1 (64%), IMP3 (85%), p53 (64%), and p16 (76%). Only ER expression was significantly higher in OSPC compared with USPCs (P<0.001). The combined ER(+)WT1(+) phenotype was present in 92% of the OSPC, whereas only 18% of the USPCs had the same phenotype (P<0.001). Furthermore, 71% of the OSPCs expressed ER(+), p53(+), WT1(+), IMP3(+), and p16(+) immunophenotype, whereas in USPCs, the tumor cells showed immunophenotypic diversity, with only 6% of the USPCs expressing reactivity to all the 5 markers (P<0.001). This study suggests that ER alone or in combination with a limited panel of markers may be used to identify the site of origin of SPCs.

p16INKa immunocytochemistry in fine-needle aspiration cytology smears of metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) may initially present with neck metastases diagnosed by fine-needle aspiration (FNA). In these patients, it is critical to locate the primary site so that targeted therapy can be administered. Nearly a quarter of HNSCC are associated with human papillomavirus (HPV) infection. The great majority of HPV-related primaries originate in the oropharynx. p16INKa (p16) functions as a surrogate marker of HPV infection. We sought to determine if expression of p16 by immunocytochemistry (ICC) in neck metastases could assist in localizing the primary site to the oropharynx. STUDY DESIGN: Diagnostic FNA cytology smears of neck metastases from 90 patients with biopsy-proven primary HNSCC were reviewed. Papanicolaou-stained slides were directly subjected to ICC, using p16 antibody. RESULTS: Twenty-seven (30%) tumors expressed p16 by ICC; 74% of these p16-positive tumors were metastases from oropharynx. There was a significantly higher proportion of p16 expression in patients with primary oropharyngeal carcinoma (47%) versus those whose primary tumor was non-oropharyngeal (15%; p = 0.0013). CONCLUSIONS: p16 expression in FNA cytology smears of metastatic HNSCC is a useful indicator of oropharyngeal origin and can be used to help localize the primary site in cases where this is not clinically evident.

Utility of TRPS1 in Malignant Effusion Cytology.

INTRODUCTION: Identifying metastatic breast carcinoma (mBC) in malignant effusion cytology (MEC) specimens is critical, as this will determine the patient's prognosis and therapeutic management. Overlapping cytomorphologic features of breast carcinoma (BC) with other neoplastic entities makes the use of sensitive and specific markers highly desirable. Recent studies have reported trichorhinophalangeal syndrome type 1 (TRPS1) as a sensitive and specific marker for primary BC and mBC. We aimed to investigate TRPS1 expression in MEC of mBC and its most common diagnostic mimickers. MATERIALS AND METHODS: A retrospective search from the pathology archives identified 82 MEC. TRPS1 expression in mBC was analyzed, and the results were compared to those in metastatic carcinoma of Müllerian origin (mMC) and metastatic pulmonary adenocarcinoma (mPAC). TRPS1 immunoperoxidase was performed on cytospin or cell block preparations, and p < 0.05 was considered significant. RESULTS: Nuclear expression for TRPS1 was evaluated and scored as positive (≥1% of tumor cells) or negative. Nuclear TRPS1 expression was seen in 100% (30/30) mBC, 72% (18/25) mMC, and 7% (2/27) mPAC. This resulted in sensitivity, specificity, positive predictive value, and negative predictive values of 100%, 61%, 60%, and 100%, respectively. CONCLUSION: TRPS1 is a sensitive marker for mBC and can be reliably performed on cytology specimens. TRPS1 expression was also identified in a significant proportion of mMC, creating a potential diagnostic pitfall. Therefore, caution should be exercised when evaluating MEC of mBC with TRPS1. Consequently, a combination of immunoperoxidase panels should be employed in this setting.

A child with BK virus infection: inadequacy of current therapeutic strategies.

In this report, we describe the development of BKVN in the native kidneys of a child with a cardiac transplant. Elevated BK viral DNA load by PCR necessitated a prolonged course of treatment with escalating doses of cidofovir. Despite a reduction in plasma BK viral load, the infection evolved into an invasive CNS disease, resulting in rhomboencephalitis. This case highlights the need for awareness of the possibility of developing multiorgan complications from BKV infection. The current treatment options for BKV tissue invasive disease are inadequate and need to be improved.

Liver mesenchymal neoplasms: something old, something new.

Histological examination of liver biopsies and resection specimens remains the gold standard to establish a definitive diagnosis of liver lesions. While hepatocellular carcinoma remains the most commonly encountered liver lesion on mass-directed biopsies, surgical pathologists must be aware of other entities that may pose diagnostic challenges, as an accurate diagnosis is key for patient management. Mesenchymal tumours of the liver are relatively uncommon, therefore many pathologists are unfamiliar with these tumours. While the clinical presentation and radiological features of these lesions often overlap, careful attention to histological clues can assist in weeding out various congeners to arrive at the most accurate diagnosis. An additional challenge when diagnosing mesenchymal tumours is the specimen type, as mass-directed core biopsies are limited and have become standard clinical practice. Besides careful attention to histological features, radiological findings and clinical history, immunohistochemical analysis and molecular studies have become of immense diagnostic value. In this review, we discuss several common and rare mesenchymal hepatic lesions as defined in the current World Health Organization (WHO) classification and most up-to-date literature. We also discuss immunohistochemistry panels and relevant molecular findings that may assist in rendering an accurate diagnosis when encountering these lesions in daily practice.

Application of the Milan System for Reporting Salivary Gland Cytopathology: A Single Institutional Experience of 354 Cases with Cytologic-Histologic Correlation.

BACKGROUND: Evaluation of salivary gland lesions is routinely done preoperatively by fine-needle aspiration cytology (FNAC). The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC), with diagnostic categories I-VI, has been recommended to standardize the reporting of salivary gland lesions by FNAC. We aimed to reclassify archival salivary gland FNAC samples using MSRSGC, correlate the samples with surgical resections, and calculate the risk of malignancy (ROM) for each category. METHODS: A total of 354 salivary gland FNAC samples (2013-2018) were reviewed. All FNAC results were retrospectively classified according to the MSRSGC. All cases had surgical follow-up. Histology was used to calculate the ROM, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy. RESULTS: The 354 aspirates were classified as: nondiagnostic (ND) 17.0% (60), non-neoplastic (NN) 1.4% (5), atypia of undetermined significance (AUS) 11.0% (39), benign neoplasm (BN) 49.4% (175), salivary gland neoplasms of unknown malignant potential (SUMP) 10.7% (38), suspicious for malignancy (SM) 3.4% (12), and malignant (M) 7.1% (25). The ROM was as follows: ND 22%, NN 20%, AUS 15%, BN 2%, SUMP 53%, SM 75%, and M 96%. The diagnostic accuracy for separating benign versus malignant neoplasms was 96%. Cytologic-histologic correlation yielded a false-negative rate of 2.7%, false-positive rate of 10.5%, PPV of 89%, NPV of 97%, sensitivity of 87%, and specificity of 98%. CONCLUSION: MSRSGC helps standardize cytology reports, provides useful information for appropriate clinical management, and ensures the best care of patients with salivary gland lesions.

Risk of malignancy associated with the diagnostic categories proposed by the Papanicolaou Society of Cytopathology for pancreaticobiliary specimens: An institutional experience.

BACKGROUND: The guidelines published by the Papanicolaou Society of Cytopathology (PSC) intend to unify the reporting language in pancreaticobiliary specimens and improve communication between cytopathologists and clinicians. The six categories in the system will determine the best management for patients. However, there is limited evidence regarding the risk of malignancy (ROM) associated with each category. METHODS: A retrospective search was performed for pancreaticobiliary fine-needle aspiration (FNA) reports with corresponding surgical follow-up. Cases were reclassified according to the PSC. The ROM, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each category. RESULTS: A total of 297 cases were identified and reclassified as: 30 nondiagnostic (category I), 45 negative for malignancy (II), 20 atypical (III), 42 neoplastic: other (IVB), 19 suspicious for malignancy (V), and 141 malignant (VI). The absolute ROM was 10% for category I, 8.9% for category II, 60% for category III, 4.8% for category IV when the neoplasms were not characterized as malignant, and 100% when categorized as malignant; 100% for category V, and 95.7% for category VI. Sensitivity, specificity, positive predictive value, and negative predictive value for neoplasia and malignancy, including categories IV to VI, were 96.6%, 88.4%, 97.5%, and 84.4%, respectively. CONCLUSIONS: The categories developed by the PSC stratify the ROM. Aspirates designated as categories V and VI had the highest ROM. Our rate of atypical category complies with the recommended rate of <10%. This scheme provides valuable information to clinicians treating patients with pancreatic lesions.