Immunohistochemistry and immunofluorescence utilization audit by subspecialty in an academic setting: A step toward stewardship.

There are immunohistochemistry (IHC) and immunofluorescence (IF) panels described in the literature and established by personal and institutional experiences that are in common use by pathologists in their daily practice. Stewardship is a difficult discussion because IHC utilization is influenced by many factors including the pathologist's experience, background, practice setting, personal bias, and medicolegal culture. We developed the methodology to audit the IHC/IF utilization in our academic subspecialty practice. We aim to share this methodology and to provide our data that can be used for consideration by other subspecialized academic practices. This analysis included a total of 63,157 specimens that were accessioned during 2022, representing 38,612 cases. The likelihood of ordering IHC/IF ranged from 1 % (in genitourinary pathology) to 59 % (in renal pathology). The average percentage of specimens with IHC/IF was 21 % for the entire practice. In cases where IHC/IF was ordered, the number of stained slides averaged 4.9 per specimen for the entire practice. The number of IHC/IF slides per specimen ranged from 1.9 (in gastrointestinal pathology) to 12.2 (in renal pathology). The highest number of antibodies ordered for a single specimen by subspecialty ranged from 11 (in cardiac pathology) to 63 (in dermatopathology). Renal pathology was the only subspecialty that had an average number of IHC/IF slides that was statistically significantly different from all other subspecialties. We described the various patterns of utilization by subspecialty and rationalized their subtle differences. We also analyzed the types of cases that exceeded the reimbursement limits set by the Centers for Medicare and Medicaid Services (CMS).

Hyaluronan/CD44 axis regulates S100A4-mediated mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis.

Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting fibrogenic signaling pathways, idiopathic pulmonary fibrosis (IPF) remains a major unsolved clinical problem. One reason for this is that available antifibrotic agents slow down but do not arrest fibrotic progression. To arrest fibrotic progression, its obligatory drivers need to be identified. We previously discovered that fibrogenic mesenchymal progenitor cells (MPCs) are key drivers of fibrotic progression in IPF, serving as cells of origin for disease-mediating myofibroblasts. IPF MPCs have high levels of nuclear S100A4, which interacts with the proteasome to promote p53 degradation and self-renewal. However, the mechanism underlying S100A4 accumulation in the nucleus of IPF MPCs remains unknown. Here we show that hyaluronan (HA) is present in the fibroblastic focus together with CD44-expressing MPCs and that ligation of CD44 by HA triggers S100A4 nuclear translocation to support IPF MPC self-renewal. The mechanism involves HA-mediated formation of a CD44/S100A4/transportin 1 complex, which promotes S100A4 nuclear import. In a humanized mouse model of pulmonary fibrosis, IPF MPC fibrogenicity was significantly attenuated by 1) knockdown of CD44 or 2) introduction of an S100A4 mutant construct that prevents S100A4 nuclear import. These data indicate that signaling through the HA/CD44/S100A4 axis is an integral component of IPF MPC fibrogenicity.

Clinicopathologic characteristics of malignant non-hematopoietic tumors first presented as an axillary mass with emphasis on occult breast carcinoma.

BACKGROUND: Non-hematopoietic malignancies first presented as an axillary mass constitute a unique clinical presentation. We investigated the incidence of various types of malignancies and aimed to define clinicopathologic variables that may assist in the diagnosis, with focus on occult breast carcinoma (OBC). DESIGN: We reviewed the pathology reports of cases with non-hematopoietic malignancies of the axillary region in our institution between 2000 and 2016. We included patients who presented first with axillary mass and with the absence of a known primary. We recorded patients' age and gender, tumor characteristics including size, histologic type, number of positive lymph nodes, and the clinical management. Then we focused on BC which were divided into OBC or primary BC (PBC). RESULTS: There were 100 cases that met our criteria (28 melanoma, 7 sarcoma and 65 carcinoma). For carcinoma cases, there were 42 BC (19 OBC, 17 PBC, and 6 possible OBC), 17 non-BC, and 6 carcinoma of unknown primary (CUP). Tumors found incidentally were more likely to be of breast primary (p = 0.01). Larger tumor size (in mm) favored melanoma or sarcoma over BC, non-BC carcinoma or CUP with median and range 61 (15, 180), 60 (23, 80), 30 (15, 75), 31 (17, 90), 26 (20, 55), respectively (p < 0.001). There were no differences in the histopathologic findings or clinical presentation. CONCLUSIONS: More than half of the patients with axillary malignancy have a tumor of non-breast origin. Therefore, clinical and pathologic studies are warranted to identify the primary site.

Mapping electrical properties heterogeneity of tumor using boundary informed electrical properties tomography (BIEPT) at 7T.

PURPOSES: To develop and evaluate a boundary informed electrical properties tomography (BIEPT) technique for high-resolution imaging of tumor electrical properties (EPs) heterogeneity on a rodent tumor xenograft model. METHODS: Tumor EP distributions were inferred from a reference area external to the tumor, as well as internal EP spatial variations derived from a plurality of relative transmit B1 measurements at 7T. Edge sparsity constraint was enforced to enhance numerical stability. Phantom experiments were performed to determine the imaging accuracy and sensitivity for structures of various EP values, as well as geometrical sizes down to 1.5 mm. Numerical simulation of a realistic rodent model was used to quantify the algorithm performance in the presence of noise. Eleven athymic rats with human breast cancer xenograft were imaged in vivo, and representative pathological samples were acquired for comparison. RESULTS: Reconstructed EPs of the phantoms correspond well to the ground truth acquired from dielectric probe measurements, with the smallest structure reliably detectable being 3 mm. EPs heterogeneity inside a tumor is successfully retrieved in both simulated and experimental cases. In vivo tumor imaging results demonstrate similar local features and spatial patterns to anatomical MRI and pathological slides. The imaged conductivity of necrotic tissue is higher than that of viable tissues, which agrees with our expectation. CONCLUSION: BIEPT enables robust detection of tumor EPs heterogeneity with high accuracy and sensitivity to small structures. The retrieved quantitative EPs reflect tumor pathological features (e.g., necrosis). These results provide strong rationale to further expand BIEPT studies toward pathological conditions where EPs may yield valuable, non-invasive biomarkers.

Case report: Salivary duct carcinoma in a patient with a germline CDH1 pathogenic variant - expanding the spectrum of hereditary cancer predisposition syndromes.

Introduction: Recently, an entity known as salivary duct carcinoma with rhabdoid features (SDC-RF) has been associated with somatic CDH1 mutations. Here we present the first known case report of conventional SDC occurring in the setting of a germline CDH1 pathogenic variant accompanied by a somatic loss of heterozygosity at the CDH1 locus. Case discussion: A 67-year-old man presented with chest and back pain and was found to have osteolytic lesions in the sternum and lumbar spine. Vertebral bone biopsies were positive for metastatic carcinoma of unknown primary. A molecular profiling assay consisting of both whole-exome next-generation sequencing (NGS) as well as immunohistochemistry (IHC) for select clinically-relevant proteins performed on the bone biopsy suggested a triple-negative (ER/PR/ERBB2 negative, by IHC), androgen receptor (AR IHC) positive tumor profile. Additionally, the assay uncovered a coding mutation in the CDH1 gene (c.1792C>T, p.R598*) with genomic loss of the second CDH1 allele. Germline testing returned positive for a heterozygous CDH1 pathogenic variant. PET-CT revealed a tumor in the neck suggestive of the primary malignancy consistent with that of salivary gland origin. The patient was initially treated with carboplatin and paclitaxel, then pembrolizumab, and finally with AR-directed therapy using leuprolide and enzalutamide. These treatments were not successful, and the patient eventually succumbed to his disease. Conclusion: Molecular testing revealed that our patient had bi-allelic inactivation of the CDH1 gene. We believe our patient developed a somatic mutation in addition to his preexisting germline CDH1 mutation that ultimately predisposed him to SDC. While previous studies have found somatic CDH1 pathogenic variants in SDC-RF, our patient was found to have a germline CDH1 pathogenic variant in the setting of conventional SDC, without rhabdoid features. This case provokes questions regarding tumor genetics and molecular profiling of SDC in patients with germline CDH1 pathogenic variants. Moreover, this case supports the notion that SDC may be the salivary counterpart of other malignancies associated with germline CDH1 pathogenic variants and may possibly expand the spectrum of tumors that arise in this familial cancer-predisposition syndrome.

Nontraumatic Pseudoaneurysm of the Deep Palmar Arch in a 10-Month-Old Infant: A Case Report.

CASE: Pseudoaneurysms of the hand are rare among the adult population and even more rare in pediatric patients. We report a case of a 10-month-old boy who presented with a nontraumatic pseudoaneurysm of the deep palmar arch, likely of congenital etiology. Magnetic resonance imaging and angiography identified the growing left hand palmar mass. Surgical excision without the need for vascular reconstruction was performed successfully with no recurrence or complications at 1-year follow-up. CONCLUSION: Surgical excision is an effective treatment for large or symptomatic palmar pseudoaneurysms of likely congenital origin. Vascular reconstruction after excision must be considered on a case-by-case basis to ensure adequate hand perfusion.

The role for endobronchial biopsy in the era of endobronchial ultrasound guided transbronchial needle aspiration for the diagnosis of sarcoidosis: a single center experience.

BACKGROUND AND AIM: Endobronchial biopsy (EBBX) has been reported to increase diagnostic yield for pulmonary sarcoidosis. The purpose of this study is to investigate the diagnostic yield for EBBX following endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). METHODS: We identified a cohort of patients in the University of Minnesota Sarcoidosis Registry who had EBBx and EBUS-TBNA as part of workup for abnormal chest imaging. Data regarding demographics, biopsy approach and technique were recorded. RESULTS: Our cohort included 37 patients (53.24±9.5, Male, 22±0.57; 3.8% were African American). In these patients who had EBBX, EBUS-TBNA was performed in 100% of patients and TBBX was performed in 2 patients (5%). EBBX was positive in 9 patients (24%) and EBUS-TBNA was positive in 34 patients (92%). TBBX was diagnostic in one of two patients. EBBX was the only diagnostic tissue in 3 of the 37 patients (8%).  Conclusion: The diagnostic yield of EBBX is lower than previously reported, with only 8% of EBBXs demonstrating granulomatous inflammation. However, instrumentation used for obtaining EBBX as well as the presence of visible lesions does influence the diagnostic yield. Studies with adequate power are needed before implementing changes in clinical practice.  When performed alongside EBUS-TBNA, EBBX did not significantly add to the diagnostic yield in sarcoidosis unless visible lesions were observed.

Analysis of vitamin D status at two academic medical centers and a national reference laboratory: result patterns vary by age, gender, season, and patient location.

BACKGROUND: Testing for 25-hydroxyvitamin D [25(OH)D] has increased dramatically in recent years. The present report compares overall utilization and results for 25(OH)D orders at two academic medical centers - one in New York and one in Iowa - in order to characterize the vitamin D status of our inpatient and outpatient populations. Results are also compared to those from a national reference laboratory to determine whether patterns at these two institutions reflect those observed nationally. METHODS: Retrospective data queries of 25(OH)D orders and results were conducted using the laboratory information systems at Weill Cornell Medical College / New York Presbyterian Hospital (WCMC), University of Iowa Hospitals and Clinics (UIHC), and ARUP Laboratories (ARUP). Chart review was conducted for cases with very high or low serum 25(OH)D levels in the WCMC and UIHC datasets. RESULTS: The majority of tests were ordered on females and outpatients. Average serum 25(OH)D levels were higher in female versus male patients across most ages in the WCMC, UIHC, and ARUP datasets. As expected, average serum 25(OH)D levels were higher in outpatients than inpatients. Serum 25(OH)D levels showed seasonal periodicity, with average levels higher in summer than winter and correlating to regional UV index. Area plots demonstrated a peak of increased 25(OH)D insufficiency / deficiency in adolescent females, although overall worse 25(OH)D status was found in male versus female patients in the WCMC, UIHC, and ARUP datasets. Surprisingly, improved 25(OH)D status was observed in patients starting near age 50. Finally, chart review of WCMC and UIHC datasets revealed over-supplementation (especially of ≥ 50,000 IU weekly doses) in the rare cases of very high 25(OH)D levels. General nutritional deficiency and/or severe illness was found in most cases of severe 25(OH)D deficiency. CONCLUSIONS: 25(OH)D status of patients seen by healthcare providers varies according to age, gender, season, and patient location. Improved 25(OH)D status was observed later in life, a finding that may reflect the previously described increased use of vitamin D-containing supplements in such populations. Severe vitamin D deficiency is much more common than vitamin D toxicity.

Intraoral salivary lymphoepithelial carcinoma: clinicopathologic and immunophenotypic characterization of 3 cases indicates elevated programmed death-ligand 1 expression.

OBJECTIVE: Intraoral salivary lymphoepithelial carcinoma (ISLEC) is a rare malignancy with programmed death-ligand 1 (PD-L1) expression levels that have been greatly understudied. We examined the clinicopathologic and immunophenotypic characteristics, including PD-L1 levels, of 3 cases of ISLEC. STUDY DESIGN: We searched the archives of 2 oral and maxillofacial pathology laboratories for specimens diagnosed as ISLEC between 1985 and 2022. We collected patient demographic and clinical data. Immunostaining for AE1/AE3, CK7, CD3, CD20, p16, p53, Ki67, and PD-L1 (SP263), as well as Epstein-Barr virus-encoded small RNAs (EBER) in situ hybridization (ISH) were performed. RESULTS: All 3 cases affected males aged 42 to 84 years (median = 61y) and involved the floor of the mouth, soft palate/uvula, and tongue. The lesions showed diffuse infiltration by non-keratinizing sheets and islands of undifferentiated carcinoma cells with associated dense lymphoplasmacytic inflammation. Immunohistochemically, all tumors showed AE1/AE3 positivity, selective p53 staining, and negativity for CK7 and p16. Ki67 highlighted 20%-80% of lesional cells. The inflammatory infiltrate comprised a mixed population of T and B lymphocytes. EBER ISH was positive in one case. All ISLECs displayed membranous, focal-to-diffuse, PD-L1 staining with tumor proportion score > 95% in two and 40-50% in the third case. CONCLUSIONS: The clinicopathologic and immunophenotypic characteristics of the cases we examined highlight the rarity of ISLEC and indicate overall high PD-L1 levels in this type of malignancy, rendering patients with ISLEC potential candidates for targeted α-PD-1/PD-L1 immunotherapy.

Exploration of INSM1 and hASH1 as additional markers in lung cytology samples of high-grade neuroendocrine carcinoma with indeterminate neuroendocrine differentiation.

BACKGROUND: Traditional neuroendocrine (NE) markers synaptophysin, chromogranin, and CD56 play an integral role in affirming the diagnosis of high-grade lung NE carcinoma, however promising markers, INSM1, and hASH1, have been identified. We investigated the utility of these markers in pulmonary cytology specimens, particularly in cases where results of traditional NE markers were equivocal. METHODS: A retrospective search of cytology cases obtained via endobronchial ultrasound (EBUS)-guided FNA revealed 26 cases of high-grade lung carcinoma where an indeterminate diagnosis of small-cell lung carcinoma (SCLC) was based on equivocal IHC staining with traditional NE markers. A separate cohort of 23 cases positive for all traditional markers with a definitive diagnosis of SCLC was also selected. Cytology cellblock sections were immunostained with INSM1 and hASH1 and analyzed using H-score methodology (score range 0-300). A score of ≥95 was considered "positive." RESULTS: INSM1 was positive in 19/24 (79.2%) of cases of high-grade lung carcinoma with indeterminate NE differentiation, while hASH1 was positive in 6/24 (25.0%). Chromogranin was seen only focally positive (<10% of cells) in 4/24 (16.7%), synaptophysin positive in 16/24 (66.7%), and CD56 positive in 14/21 (66.7%). Among unambiguous cases, INSM1 was positive in all cases with an average score of 233.9, while hASH1 was positive in 21/23 (91.3%) with an average score of 196.3. CONCLUSION: Compared with traditional NE stains and to hASH1, INSM1 was expressed in a higher number of cases of high-grade lung NE carcinomas in cytology cellblock specimens, making it a superior, more sensitive NE marker.

Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas.

Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model.

Growing evidence indicates antibody-dependent cellular cytotoxicity (ADCC) contributes to the clinical response to monoclonal antibody (mAb) therapy of lymphoma. Recent in vitro analysis suggests C3b can inhibit mAb-induced natural killer (NK)-cell activation and ADCC. Further studies were conducted to assess the effect of C3 depletion on mAb-induced NK activation and therapy of lymphoma. Normal human serum inhibited the ability of rituximab-coated lymphoma cells to activate NK cells as previously reported. Serum did not inhibit NK-cell activation when it was preincubated with cobra venom factor (CVF) to deplete C3. Similar results were found when transudative pleural fluid or nonmalignant ascites was used as surrogates for extravascular fluid, suggesting the inhibitory effect of complement may be present in the extravascular compartment, in which many malignant lymphocytes reside. In vivo, C3 was depleted before mAb treatment in a syngeneic murine model of lymphoma. Survival of lymphoma-bearing mice after treatment with CVF plus mAb and with a human C3 derivative with CVF-like functions (HC3-1496) plus mAb was both superior to that of mAb alone. These studies show that complement depletion enhances NK-cell activation induced by rituximab-coated target cells and improves the efficacy of mAb therapy in a murine lymphoma model.

Performance of Ventana SP263 PD-L1 assay in endobronchial ultrasound guided-fine-needle aspiration derived non-small-cell lung carcinoma samples.

BACKGROUND: Introduction of programmed death-ligand 1 (PD-L1) inhibitors has significantly changed the treatment landscape of non-small-cell lung carcinomas (NSCLC). Since endobronchial ultrasound guided fine-needle aspiration (EBUS FNA) has become the primary diagnostic and staging modality for NSCLC, this study was pursued to determine the adequacy of Ventana SP263 PD-L1 assay in cytology cell blocks. DESIGN: Fifty NSCLC cases with cytology and corresponding histology specimens obtained between 2014 and 2018 were identified. After assessing for adequacy (100 or more tumor cells), forty cases were selected for Ventana SP263 PD-L1 immunohistochemistry (IHC) assay and assessed for tumor proportion scores (TPS) and staining intensity scores (SIS) and analyzed for concordance. RESULTS: Of the 40 matched pairs 33 (82.5%) showed concordant PD-L1 expression. On cytology, 32 cases were positive (8 high-expressors and 24 low-expressors) of which 27 were concordant and 5 discordant with matched histology specimens. On histology, 29 cases were positive (7 high-expressor and 22 low-expressors) while 11 cases were negative for PD-L1 expression of which 6 had concordant negative cytology. The intraclass correlation coefficients (ICC) for TPS was 0.81 with 95% confidence interval (0.68, 0.9) and for the SIS, it was 0.78 with 95% CI (0.62, 0.88), both considered as having excellent agreement. CONCLUSION: With an overall concordance rate of 82.5% between cytology and histology specimen, this study demonstrates the feasibility of PD-L1 IHC with SP263 clone on cytology samples of NSCLC and adds to a growing body of evidence validating the use of cytology cell blocks for PD-L1 expression testing.

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review.

Small-cell lung carcinoma (SCLC) is one of the most aggressive solid tumors, and the prognosis has not improved significantly in 25 years. Despite a recent understanding of the genomic aberrations seen in SCLC, these insights have not led to any breakthroughs in treatment. We present a patient with SCLC harboring a novel MYCL1 fusion protein who experienced a prolonged disease course due to the use of Aurora A kinase inhibitor and subsequently nivolumab. MYC family genes are master regulators of several cellular pathways including proliferation, differentiation, and apoptosis and recently have been shown to be involved in tumor immune evasion. Large studies have shown that a significant proportion of patients with SCLC have amplification or overexpression of MYC family genes. Preclinical data have exposed vulnerability of MYC-driven tumors to Aurora kinase inhibitors, bromodomain and extraterminal domain inhibitors, and recently to immune checkpoint blockers. Further studies using these agents with selective enrolling of patients with MYC-altered tumors are warranted to exploit these vulnerabilities.

Pulmonary vein occlusion and veno-occlusive disease in a bilateral lung transplant patient: A case report.

A pulmonary vein occlusion and biopsy proven pulmonary veno-occlusive disease (PVOD) and hemangiomatosis is found in a bilateral lung transplant patient. A 61-year-old male presents with dyspnea and chest pain with minimal exertion at routine follow up on post-transplant day of 50. Chest CT demonstrates new occlusion of bilateral superior pulmonary veins and diffuse pulmonary edema. Pulmonary vein occlusion is confirmed by trans-esophageal echocardiogram, and PVOD and hemangiomatosis is corroborated with lung biopsy. Normal pulmonary capillary wedge pressure (PCWP) and reduced DLCO are also consistent with PVOD. Vigilant evaluation of large pulmonary venous thrombus is as important as of arterial thrombus in a postsurgical transplant status. A dedicated protocol of pulmonary venous phase scan would be beneficial to identify subtle pulmonary venous abnormalities. Although PVOD/PCH is normally considered in patients with nonspecific PAH symptoms, lacking of direct manifestation of PAH should not dismiss the diagnosis of PVOD/PCH, particularly in lung transplant individuals with large pulmonary vein occlusion, progressive respiratory symptoms, DLCO abnormalities, and pulmonary congestion since it may represent a wide spectrum of occlusive vascular disease.

Mediastinal ganglioneuroma diagnosed by transesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA).

Ganglioneuromas are rare benign tumors that arise from the sympathetic nerve fibers and represent the final maturation stage of neuroblast tumors. The most common sites of involvement in the body include posterior mediastinum, followed by retroperitoneum, adrenal gland, and soft tissues of the head and neck. In the mediastinum, this tumor is most frequently located in posterior compartment, together with other neurogenic tumors. The reports of mediastinal ganglioneuroma diagnosed by fine needle aspiration (FNA), especially endoscopic ultrasound-guided FNA (EUS-FNA) are very sparse. We describe the clinical, radiologic, cytologic, gross and histologic features of mediastinal ganglioneuroma diagnosed by transesophageal endoscopic ultrasound-guided fine needle aspiration.

Xanthogranulomatous Sialadenitis, an Uncommon Reactive Change is Often Associated with Warthin's Tumor.

Xanthogranulomatous sialadenitis (XGS) is rare in salivary glands and only reported in the literature as single cases. Here we report a cohort of four cases with XGS and summarize the clinicopathologic features of these cases. All four patients had persistent mass lesions concerning for neoplasm. In two patients (patient 1 and 3), the initial fine needle aspirations (FNAs) contained oncocytic cells consistent with or suspicious for Warthin's tumor, but follow-up FNAs showed only inflammation and/or debris indicating tumor infarction after FNA. All patients eventually had surgical resection. Histologically, all cases contained abundant macrophages with necrosis and fibroblastic proliferation. Warthin's tumor with a grossly identifiable tumor nodule (0.7 cm) was noted in patient 1 and a microscopic focus (0.2 cm) of Warthin's tumor was identified in patient 3. No identifiable tumor was observed in patient 2 and 4. There are a total of 10 XGS cases in the literature (including four from this series) and Warthin tumor was identified in 50% of reported cases of XGS, suggesting that XGS is an uncommon reactive process to spontaneous or procedure-induced infarction of Warthin tumor. As a diagnostic mimicker for malignancy, a thorough examination and generous sampling of surgical resection specimen is warranted, although a benign salivary gland neoplasm, commonly Warthin's tumor, is often identified.

Single-cell RNA sequencing reveals that lung mesenchymal progenitor cells in IPF exhibit pathological features early in their differentiation trajectory.

In Idiopathic Pulmonary Fibrosis (IPF), there is unrelenting scarring of the lung mediated by pathological mesenchymal progenitor cells (MPCs) that manifest autonomous fibrogenicity in xenograft models. To determine where along their differentiation trajectory IPF MPCs acquire fibrogenic properties, we analyzed the transcriptome of 335 MPCs isolated from the lungs of 3 control and 3 IPF patients at the single-cell level. Using transcriptional entropy as a metric for differentiated state, we found that the least differentiated IPF MPCs displayed the largest differences in their transcriptional profile compared to control MPCs. To validate entropy as a surrogate for differentiated state functionally, we identified increased CD44 as a characteristic of the most entropic IPF MPCs. Using FACS to stratify IPF MPCs based on CD44 expression, we determined that CD44hi IPF MPCs manifested an increased capacity for anchorage-independent colony formation compared to CD44lo IPF MPCs. To validate our analysis morphologically, we used two differentially expressed genes distinguishing IPF MPCs from control (CD44, cell surface; and MARCKS, intracellular). In IPF lung tissue, pathological MPCs resided in the highly cellular perimeter region of the fibroblastic focus. Our data support the concept that IPF fibroblasts acquire a cell-autonomous pathological phenotype early in their differentiation trajectory.

A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma.

PURPOSE: Complement may play a role in the clinical response to rituximab and other monoclonal antibody-based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA([276]) polymorphism and the clinical response to rituximab in patients with follicular lymphoma. EXPERIMENTAL DESIGN: Genotyping for C1qA([276A/G]) was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis. RESULTS: Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA([276]) genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects. CONCLUSIONS: Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.

Acute exacerbation of interstitial lung disease after procedures.

Interstitial lung disease (ILD) is a category of diffuse parenchymal lung diseases characterized by inflammation and/or fibrosis. The best characterized ILD is idiopathic pulmonary fibrosis (IPF). Acute exacerbation of IPF is a dreaded occurrence with grim prognosis and suboptimal treatment options. There have been recent reports that acute exacerbation can occur in other ILDs (AE-ILD). Of note, some of these acute exacerbations follow lung procedures. This review summarizes the available information on AE-ILD and discusses the procedures reported to cause AE-ILD. We also discuss proposed mechanisms, risk factors, treatment and prognosis. This review should help to inform decision-making about risks versus benefits of procedures that are commonly recommended to diagnose ILD.