The Utility of Fine Needle Aspiration (FNA) Biopsy in the Diagnosis of Mediastinal Lesions.

Fine needle aspiration is a minimally invasive, low-morbidity, and cost-efficient technique for the sampling of mediastinal lesions. Additionally, ancillary testing on FNA samples can be used for the refinement of diagnoses and for treatment-related purposes (flow cytometry, cytogenetics, immunohistochemistry, and molecular diagnostics). Mediastinal lesions, however, can show a variety of lineages and morphologic features, giving rise to diagnostic dilemmas. As a result, the differential diagnosis can vary widely and becomes especially challenging due to the smaller sample size on FNA and the variability in component sampling. For appropriate patient management and to determine the correct treatment strategies, accurate pathologic diagnoses are paramount. In this review, we present the cytomorphologic features together with the immunophenotypic findings of mediastinal lesions, with emphasis on the diagnostic challenges and pitfalls in FNA cytology samples, including smears and cell block sections.

Particulate Matters Affecting lncRNA Dysregulation and Glioblastoma Invasiveness: In Silico Applications and Current Insights.

With a reported rise in global air pollution, more than 50% of the population remains exposed to toxic air pollutants in the form of particulate matters (PMs). PMs, from various sources and of varying sizes, have a significant impact on health as long-time exposure to them has seen a correlation with various health hazards and have also been determined to be carcinogenic. In addition to disrupting known cellular pathways, PMs have also been associated with lncRNA dysregulation-a factor that increases predisposition towards the onset or progression of cancer. lncRNA dysregulation is further seen to mediate glioblastoma multiforme (GBM) progression. The vast array of information regarding cancer types including GBM and its various precursors can easily be obtained via innovative in silico approaches in the form of databases such as GEO and TCGA; however, a need to obtain selective and specific information correlating anthropogenic factors and disease progression-in the case of GBM-can serve as a critical tool to filter down and target specific PMs and lncRNAs responsible for regulating key cancer hallmarks in glioblastoma. The current review article proposes an in silico approach in the form of a database that reviews current updates on correlation of PMs with lncRNA dysregulation leading to GBM progression.

COVID-19 Infection in Fingolimod- or Siponimod-Treated Patients: Case Series.

BACKGROUND AND OBJECTIVES: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. METHODS: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020. RESULTS: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. DISCUSSION: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Pitfalls of FNA diagnosis of thymic tumors.

BACKGROUND: Fine-needle aspiration (FNA), a minimally invasive and cost-effective procedure, often is used in the initial diagnosis of thymic lesions. However, the diagnosis can be challenging. Knowledge of the diagnostic pitfalls is important to improve diagnostic accuracy. METHODS: The authors retrospectively searched the pathology database of The University of Texas MD Anderson Cancer Center for FNA cases using the keywords "thymoma" or "thymic" in cytologic diagnoses or in corresponding final histologic diagnoses rendered from January 2002 to June 2018. The authors reviewed the FNA diagnostic accuracy and pitfalls in comparison with the final histologic diagnoses. RESULTS: A total of 118 FNA cases were identified from 115 patients. The FNA diagnoses were concordant with the final pathologic diagnoses in 110 cases (93.2%), including thymoma (97 cases), atypical thymoma (5 cases), and thymic carcinoma (8 cases). Discrepant FNA and final diagnoses were noted in 8 tumors (6.8%): thymoma versus atypical thymoma/thymic carcinoma (3 tumors), thymoma versus lymphoma (2 tumors), suspicious for lymphoma versus thymoma (1 tumor), and T-lymphoblastic lymphoma versus thymoma (2 tumors). Factors contributing to misinterpretation included intrinsic limitations of the FNA sample (sampling error and a lack of histologic architecture information) and similarities of the cytologic and immunophenotypic features of lymphocyte-rich thymoma and T-lymphoblastic lymphoma. CONCLUSIONS: An accurate FNA diagnosis of thymic tumors can be rendered in the majority of cases. Diagnostic pitfalls can be encountered in rare cases. It is important to handle each case carefully to avoid erroneous diagnoses that may lead to inappropriate treatment.

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

OBJECTIVES: To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint. METHODS: Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2-year relapses and BVL explained by 6-month log-transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects. RESULTS: At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8-247]; placebo (n = 114) 26 [8-159], P < 0.001). NfL at 6 months correlated with number of relapses (r = 0.25, P < 0.001), 6-month CDW (hazard ratio 1.83, P = 0.012), active lesions (r = 0.46, P < 0.001), and BVL (r = -0.41, P < 0.001) at Month-24. The PTE (95% CI) on 24-month relapses and BVL explained by 6-month NfL was 25% (8-60%) and 60% (32-132%), and by 6-month active lesions was 28% (11-66%) and 45% (18-115%), respectively. Assuming a 20-40% treatment-related reduction in NfL levels, 143-28 patients per arm will be required. CONCLUSIONS: Blood NfL may qualify as an informative and easy-to-measure endpoint for future Phase 2 clinical studies that captures both inflammatory- and noninflammatory-driven neuroaxonal injury in RRMS.

Blood neurofilament light chain as a biomarker of MS disease activity and treatment response.

OBJECTIVE: To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis. METHODS: We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-ß-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes. RESULTS: At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: -0.78% [-1.02 to -0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments). CONCLUSIONS: Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial.

We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.

Computed tomography and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography findings in adrenal candidiasis and histoplasmosis: two cases.

We report the contrast-enhanced computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography findings in adrenal histoplasmosis and candidiasis. Both demonstrated bilateral hypermetabolic heterogeneous adrenal masses with limited wash-out on delayed CT. Adrenal candidiasis has not been previously reported, nor have the CT wash-out findings in either infection. The adrenal imaging findings are indistinguishable from malignancy, which is more common; but in this setting, physicians should be alert to the differential diagnosis of fungal infections, since it can be equally deadly.

Fine-needle aspiration detects primary neuroendocrine carcinoma of the breast in a patient with breast implants.

Breast augmentation with implantation represents a challenge for subsequent radiographic imaging and pathological sampling. Fine-needle aspiration biopsy (FNAB) is an excellent technique to sample suspicious lesions that are adjacent to fragile implants. We report a case of a 51-year-old woman with breast implants presenting with an initial diagnosis of fibroadenoma by imaging studies. A definite diagnosis of mammary carcinoma with plasmacytoid cells was made on ultrasound (US)-guided FNAB of the breast mass with rapid on-site evaluation which initiated core needle biopsy of the mass and subsequent mastectomy with sentinel lymph node biopsy. Our case exemplifies the role of US-guided FNAB for the initial investigation of breast masses in patients with implants. In addition, the case illustrates the cytomorphological features of the tumor cells in primary neuroendocrine carcinoma of the breast.

A case series and literature review of Merkel cell carcinoma metastasizing to pancreas.

BACKGROUND: Merkel cell carcinoma is a rare aggressive tumor arising from the mechanoreceptors of the epidermis with a relative higher mortality rate stage for stage than melanoma. Microscopically, the cells appear similar to small cell lung cancer, but they specifically stain positive for CK20 and are negative for TTF-1. It is rarely known to metastasize to the pancreas. AIMS: To report four cases of Merkel cell carcinoma metastasizing to pancreas and compare them to previously reported patients. METHODS: We performed a retrospective review of all patients who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a suspected pancreatic lesion between January 2004 and December 2012. We reviewed other reported cases with a literature search using PubMed, Embase, and Scopus. RESULTS: Four male patients with mean age of 66 years were found to have metastatic disease in the pancreas on average 29 months after initial diagnosis of MCC. Two cases were diagnosed with EUS-FNA and two with PET-CT. Three patients had multifocal pancreatic involvement which has not been previously described. All four patients died within 3-9 months following tumor spread to the pancreas. Merkel cell carcinoma rarely metastasizes to the pancreas with only 10 cases being described in the medical literature. CONCLUSIONS: EUS-FNA is an effective tool that can be utilized in diagnosing pancreatic masses. Differentiating metastatic pancreatic tumors, especially Merkel cell carcinoma from primary pancreatic tumor is useful as systemic therapy is an option in pancreatic adenocarcinoma, but is ineffective in metastatic Merkel cell carcinoma.

Evolving role of endoscopic ultrasonography-guided fine-needle aspiration in tumor staging and treatment of patients with carcinomas of the upper gastrointestinal tract.

INTRODUCTION: Treatments such as neoadjuvant chemotherapy and endoscopic mucosal resection for upper gastrointestinal carcinomas (UGC) necessitates preoperative staging evaluation of lymph nodes. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) of lymph nodes provides more accurate staging than EUS alone. Our study investigates the role of EUS-FNA in the staging/treatment of patients with UGC. MATERIALS AND METHODS: We searched our database for patients who had EUS-FNA staging of lymph nodes for UGC over 1 year. The cytologic diagnoses were compared with clinical, radiographic, EUS-determined staging, and patient follow-up data. All EUS/EUS-FNA procedures used a standard radial and/or linear echo endoscope. Direct smears from the aspirated material were stained by Papanicolaou and Diff-Quik methods. RESULTS: We studied 84 patients with esophageal or gastroesophageal junction carcinomas and 15 patients with gastric carcinomas. EUS-FNA confirmed N0 status for 100% of patients with T1 and T2 tumors and for 93% of patients with T3 tumors. Patients with T1N0 carcinomas confirmed by EUS were selected for endoscopic mucosal resection. All patients with gastric carcinomas had EUS-determined stage T3 and above tumors. Based on primary tumor stage, all patients with gastric carcinomas received neoadjuvant chemotherapy. CONCLUSIONS: Cytologic diagnosis by EUS-FNA agreed with EUS nodal staging in 77% of the patients with UGC. EUS-FNA was useful to select patients with T1N0 esophageal or gastroesophageal junction carcinomas for endoscopic mucosal resection. EUS-FNA did not contribute significantly in treatment of patients with higher stage tumors whose disease was down-staged to N0 by EUS-FNA. These patients received neoadjuvant chemotherapy based on the status of the primary tumor.

Fine-needle aspiration cytology of sclerosing adenosis of the breast: a retrospective review of cytologic features in conjunction with corresponding histologic features and radiologic findings.

We retrospectively reviewed 25 fine-needle aspiration cases of sclerosing adenosis of the breast in conjunction with histologic features of the paired core-needle biopsy and radiologic findings. The original cytologic diagnoses were benign (n = 19), focally atypical (n = 3), and suspicious for carcinoma (n = 3). The frequent features, although not specific, were low-to-moderate cellularity, bland epithelial cells that focally formed cohesive groups/tubules or occasionally discohesive clusters or individual cells, and fragments of dense fibrous stroma. Some tubules had an angulated configuration. Myoepithelial cells were present in all cases but were scant or absent in small epithelial groups. These cytologic features closely reflected the histologic appearances (ie, compressed and attenuated tubules and sclerotic stroma), but may cause overinterpretation on cytologic smears, especially when angulated tubules, discohesive or individual epithelial cells, scanty myoepithelial cells, and nuclear atypia are noted concurrently. Familiarity with its cytologic features may prevent false-positive diagnosis. Histologic confirmation is recommended for difficult cases.

Use of the monoclonal antibody MOC-31 as an immunomarker for detecting metastatic adenocarcinoma in effusion cytology.

BACKGROUND: MOC-31 is an established immunologic marker with which to detect adenocarcinomas. The objective of the current study was to evaluate the use of MOC-31 in the diagnosis of metastatic adenocarcinoma in effusion specimens. METHODS: The authors evaluated cytologic specimens of effusions/washings in which MOC-31 immunostaining was performed on unstained cell block sections or Papanicolaou-stained cytospin preparations. Membranous staining with or without cytoplasmic staining was considered to be positive. The immunostaining results were correlated with the cytologic diagnoses and clinical follow-up data. RESULTS: A total of 215 effusions and washings were identified (cell blocks in 162 cases, cytospin preparations in 53 cases, and both in 2 cases in which MOC-31 immunostaining was performed). A total of 94 (44%) of the 215 cases were found to be positive for malignancy, including 87 metastatic adenocarcinomas. Specimens were positive for MOC-31 in 76 (87%; 55 cell blocks and 21 cytospin preparations) of 87 cases of metastatic adenocarcinoma. Eleven cases of metastatic adenocarcinoma were found to be negative for MOC-31 (4 cases from lung tumors, 2 from stomach tumors, 2 from colon tumors, 2 from breast tumors, and 1 from a renal tumor). Minimal and/or focal cytoplasmic staining for MOC-31 was noted in 13% of cases of reactive mesothelial cells/mesothelioma. The sensitivity of MOC-31 for metastatic adenocarcinoma was 89%, the specificity was 100%, the negative predictive value was 92%, and the positive predictive value was 100%. CONCLUSIONS: MOC-31 alone was found to be highly sensitive for distinguishing reactive mesothelial cells/mesothelioma from metastatic adenocarcinoma in effusion specimens. Interpreting membranous MOC-31 staining as positive can help prevent confusion between reactive mesothelial cells/mesothelioma and metastatic adenocarcinoma. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.

Endobronchial ultrasound-guided transbronchial needle aspiration biopsy is useful evaluating mediastinal lymphadenopathy in a cancer center.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy is used to stage mediastinal lymph nodes in cancer patients to optimize treatment strategies. In this retrospective study, the authors determined the utility of EBUS-TBNA biopsy in the evaluation of mediastinal lymphadenopathy at a high-volume cancer center. MATERIALS AND METHODS: The pathology database was searched for all patients who had undergone EBUS-TBNA biopsy of mediastinal lymph nodes over a one-year period. Cytologic diagnoses were correlated with clinical histories, subsequent resection, and clinical follow-up data. RESULTS: Of 928 lymph node samples, 226 (24%) were diagnosed as malignant, 4 (0.4%) were suspicious for malignancy, 9 (1%) were atypical, 640 (69%) were benign, and 47 (5%) were insufficient for evaluation. In 89 (9.6%) cases, the patients had surgical resection. There was one false positive, in which the primary tumor contained infiltrating lymphocytes, had been sampled. There were five false-negative cases, which resulted from sampling errors, including two with micrometastases. The sensitivity, specificity, and positive and negative predictive value rates for EBUS-TBNA biopsy in the evaluation of mediastinal lymph nodes were 68.7% and 98.6% and 91.6% and 93.5%, respectively on a per lymph node basis. The overall clinical sensitivity, specificity, and positive and negative predictive value rates after one year clinical/radiological and histologic follow-up were 97%, 99.3%, 96.7% and 99.4%, respectively. CONCLUSIONS: EBUS-TBNA biopsy is a sensitive and specific method for evaluating mediastinal lymphadenopathy in patients with lung and other primary tumors.

Strongyloides colitis is a lethal mimic of ulcerative colitis: the key morphologic differential diagnosis.

Strongyloides stercoralis colitis is a severe, but easily curable, form of strongyloidiasis that carries a high mortality rate if untreated. Autoinfection characteristic of Strongyloides stercoralis frequently makes the infection a life-long disease unless it is effectively treated. Our experience with 4 cases of Strongyloides colitis prompted us to assess the clinical outcome of the disease by literature review. In this case series, the misdiagnosis and resultant mortality rates of Strongyloides colitis are 52% and 39.1%, respectively. A low index of suspicion and morphologic resemblance to ulcerative colitis were the main sources of diagnostic error. Ulcerative colitis alone accounted for 38.5% of the erroneous diagnoses. Features of Strongyloides colitis that contrast with those of ulcerative colitis include (1) skip pattern of the inflammation, (2) distal attenuation of the disease, (3) eosinophil-rich infiltrates, (4) relative intact crypt architecture, and (5) frequent involvement of submucosa. We also found that history of steroid therapy, chronic colitis refractory to conventional immune-modifying management, and endoscopic finding of distal attenuation of the colitis are helpful clues. It is also our experience that if Strongyloides colitis is included in the differential diagnosis, the correct diagnosis can usually be made. Current therapy with ivermectin or albendazole is very effective at a cure rate greater than 98%. We believe that the misdiagnosis and mortality rates of this curable, but often, unnecessarily deadly, infectious disease are alarming and warrant efforts to increase the awareness of the disease.