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‐β 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‐β could be a predictive biomarker for response to pembrolizumab.
Pembrolizumab has antitumor activity with tolerable toxicity in patients with advanced hepatocellular carcinoma. Plasma TGF‐β could be a predictive biomarker for response to pembrolizumab.
Brunner's gland adenoma (hyperplasia) (BGA/H) is a benign gastrointestinal lesion, usually asymptomatic and frequently detected incidentally by endoscopy as a submucosal nodule. Most BGA/Hs are ...diagnosed by their typical cytological morphology and immunohistochemical features, characterized by monomorphic cells arranged as loosely clusters of epithelial cells with abundant, clear, and granular cytoplasm, eccentrically located nuclei, and immunoreactivity for MUC‐6. The combination of the clinical and pathological features is essential for rendering a correct diagnosis. Herein, we report two cases of BGA/H, including their cytologic and histologic features, and a literature review of the clinicopathologic findings along with its differential diagnoses.
Secondary mucosal colonisation by a carcinoma originating from a distant site is a pattern of metastasis to the intestines and hepatobiliary tract and a mimic of primary neoplasia. Although ...endometriosis is considered benign, its ability to spread widely underscores its quasi-neoplastic nature. After noting that endometriotic glands can colonise the colonic mucosa along the basement membrane, mimicking metastatic disease, we conducted an intradepartmental review of intestinal specimens showing endometriosis obtained from 2016 to 2023 to characterise and quantify the incidence of this phenomenon.
Material from 38 lower gastrointestinal specimens with a primary or ancillary diagnosis of endometriosis was identified from our surgical pathology database. Slides were reviewed, documenting the extent and micro-anatomic location affected by endometriosis, with a focus on identifying examples showing mucosal colonisation.
The most common site of involvement was the distal colon (23 cases; 11 of rectum, 9 of sigmoid colon and 3 of rectosigmoid) followed by the appendix (N=10), cecum (N=2), small intestine (N=2) and 'colon not otherwise specified' (N=1). Mucosal involvement was identified in eight cases (21%), half of which demonstrated seamless colonisation of the epithelium by endometriotic glands. In two of these, the procedure was prompted by the presence of a rectal mass or stricture with concern for malignancy.
Endometriosis occasionally (4/38; 10.5%) colonises colonic epithelium, potentially mimicking a metastasis or intraepithelial neoplasia/dysplasia. Although unusual, this phenomenon was observed in half of specimens from patients with mucosal involvement in whom a mass or stricture suggested malignancy, a potentially misleading pattern of endometriosis.
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.
PLAG1 immunocytochemistry is useful for the diagnosis of pleomorphic adenoma when strong/diffusely positive and can be reliably performed directly on alcohol‐fixed conventional smears and liquid‐based cytology specimens. It may help enhance diagnostic accuracy in challenging cases and reduce indeterminate diagnoses.
Background
ThyroSeq assesses the probability of malignancy (POM) in thyroid fine‐needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated ...whether defined AUS subcategories are associated with specific molecular alterations, the molecular‐derived risk of malignancy (MDROM), and the risk of malignancy (ROM).
Methods
Fine‐needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC‐C), architectural atypia (FC‐A), both cytologic and architectural atypia (FC‐CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p < .05 was considered significant.
Results
The final analysis included 541 cases subdivided into 233 with FC‐A, 104 with FC‐C, 116 with FC‐CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC‐A, 20.5% FC‐C, 33.8% FC‐CA, and 14.4% PHC. Histologic follow‐up was available for 155 (28%) AUS cases with a follow‐up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC‐CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC‐CA subcategory. Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features was significantly more frequent in the FC‐C subcategory.
Conclusions
The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management.
Fine‐needle aspiration cytology subcategories of atypia of undetermined significance have been associated with different probabilities of malignancy and risks of malignancy and are characterized by different molecular alterations. Molecular results and an awareness of various cancer probabilities within atypia of undetermined significance subcategories can allow more tailored management.
Background
Fine‐needle aspiration cytology (FNAC) is generally the initial sampling method for salivary gland neoplasms. The cytomorphologic features of acinic cell carcinoma (AciCC) of salivary ...gland can overlap with other neoplastic and nonneoplastic entities. AciCCs harbor a recurrent t(4;9) rearrangement with upregulation of nuclear receptor subfamily 4 group A member 3 (NR4A3). NR4A3 protein overexpression has been shown to be highly sensitive and specific for the diagnosis of AciCC in histologic specimens and cell block preparations. However, data on NR4A3 immunocytochemistry (ICC) on conventional smears or liquid‐based cytology are limited.
Methods
The authors identified 18 FNAC of histologically proven AciCC cases between 2013 and 2019. FNAC samples of diagnostic mimickers were likewise retrieved and included in the study cohort for comparison. The NOR1/NR4A3 mouse monoclonal antibody was applied directly to FNAC slides using a standard ICC technique.
Results
The cohort included ethanol‐fixed Papanicolaou‐stained cytologic smears and liquid‐based preparations from 18 AciCC, one secretory carcinoma, four mucoepidermoid carcinomas, four salivary duct carcinomas, five pleomorphic adenomas (PA), five Warthin tumors, five oncocytomas, one oncocytic hyperplasia, and five nonneoplastic salivary gland cases. Strong nuclear staining for NR4A3 was present in all AciCC, weak nuclear staining was present in one PA, and all other non‐AciCC were negative (sensitivity, 100%; specificity, 97%).
Conclusions
NR4A3 ICC can be used directly on FNAC conventional smears and liquid‐based cytology to reliably distinguish AciCC from its mimickers. This marker may be useful in cases where a cell block preparation is unavailable or inadequate.
NR4A3 immunocytochemistry can be used directly on fine‐needle aspiration cytology conventional smears and liquid‐based cytology to reliably distinguish acinic cell carcinoma from its mimickers. This may be useful in cases where a cell block preparation is unavailable or inadequate.
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.
Assessing the atypia of undetermined significance rate in the context of positive call rate and time serves as a valuable metric for evaluating cytopathologists proficiency and overall laboratory performance and helps identify trends to provide valuable feedback.
Intraductal papillary neoplasm of the bile duct(IPNB) is a rare bile duct neoplasm mostly found in far eastern nations where hepatolithiasis and clonorchiasis infections are endemic. In western ...countries,it is very rare and the etiology is unknown. In this article,we report the first IPNB patient we encountered in our clinic and a literature review. The patient is a 38-yearold female with a history of choledocholithiasis who presented with obstructive jaundice. She was found to have a papillary mass at the junction of the right hepatic duct and common hepatic duct with six masses in the liver parenchyma. The immunophenotypic and histologic features of the tumor are consistent with IPNB,gastric subtype. The patient had a partial hepatectomy and has been receiving palliative chemotherapy. In a search of Pub Med database,we collected 354 IPNB patients reported in 22 articles. In these patients,52.8% were from Japan and 27.7% were from western countries including the United States(11.0%). The age of the patients ranged from 35 to 80 years old with an average of 64.6. Male/female ratio was 1.5. Macroscopically,57.5% of the tumors were in the left lobe and 29.5% were in the right lobe. The average size of the tumor were 4.2 cm at the time of diagnosis. Histologically,pancreato-biliary subtype accounted for 41.8%,intestinal 28.0%,gastric 13.5% and oncocytic 16%. An invasive component is most often present in the pancreato-biliary and gastric subtypes. Despite recent advanced technologies,diagnosis of IPNB is still challenging,especially in western countries due to its rarity. Defined clinicopathologic features are in demand for the accurate diagnosis and proper treatment.
Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease ...(GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett’s esophagus to esophageal adenocarcinoma are also discussed.
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.
PDF
