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The chemokine CXCL4 activates myeloid cells and contributes to the pathogenesis of inflammatory and fibrotic diseases. One mechanism of CXCL4 action is binding of nucleic acids to promote their internalization and activation of endosomal TLRs. However, the signaling pathways and receptors that mediate myeloid cell responses to CXCL4 alone are not well characterized. Here, we report that in primary human monocytes, CXCL4 activated NF-κB and a TBK1-JNK signaling axis that drive the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also RIPK3-dependent necroptosis. Surprisingly, six distinct lines of evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. However, in contrast to the canonical TLR4 agonist LPS, CXCL4 did not effectively activate an autocrine IFN response or IL-12 family genes, even after IFN-γ priming of monocytes. In accord with its role in inducing chemokine and inflammatory gene expression, CXCL4 regulated neutrophil and macrophage infiltration into skin wounds, and promoted wound healing in a mouse model. Our findings suggest that CXCL4 modulates the profile of TLR4 responses to induce a macrophage phenotype divergent from LPS-activated cells, provide new insights into mechanisms by which CXCL4 activates human monocytes, and implicate CXCL4 in regulation of skin wound healing.

Solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) are distinctive entities. However, due to overlapping morphologies, distinguishing them remains a diagnostic challenge. Our study investigates the utility of immunohistochemistry for nuclear lymphoid enhancer binding factor 1 (LEF1) and paired box gene 8 (PAX8) in differentiating these 2 entities. LEF1 and PAX8 immunohistochemistry were performed on fine-needle aspiration cell blocks and surgical resection specimens diagnosed as SPN or PanNET at our institution from January 2007 to August 2016. Eight SPN and 25 PanNET cell blocks and 17 SPN and 34 PanNET surgical resection specimens were examined. On cell blocks, positive staining for LEF1 had high frequency, sensitivity, and specificity for SPN (88%, 88%, and 88%) as did positive staining for PAX8 for PanNET (76%, 76%, and 75%). The findings on surgical resection specimens were consistent with those from cell blocks (LEF1+ in SPN: 100%, 100%, and 97%; PAX8+ in PanNET: 59%, 59%, and 100%). A combined LEF1+/PAX8- phenotype showed high sensitivity and specificity for SPN (cell block: 63% and 100%; surgical specimen: 100% and 98%) as did a LEF1-/PAX8+ phenotype for PanNET (cell block: 64% and 100%; surgical specimen: 59% and 100%). SPN and PanNET exhibit opposite immunophenotypic profiles with LEF1+/PAX8- in SPN and LEF1-/PAX8+ in PanNET. The combination of these 2 stains provides an effective means of distinguishing these 2 entities.

The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged40 years of age.A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome.The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings.Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

BACKGROUND Primary salivary gland-type tumors of the tracheobronchial tree are rare; their cytologic features have been seldom reported. We aim to describe the clinical and cytomorphologic features of tracheobronchial salivary gland-type tumors diagnosed by transbronchial fine needle aspiration (TBNA) at our institution, and correlate the findings with a corresponding surgical specimen. METHODS We searched our laboratory information system to identify patients with a primary salivary gland-type neoplasm of the tracheobronchial tree diagnosed by TBNA and with a corresponding surgical pathology specimen, over 10 years. RESULTS The study cohort consisted of 11 patients (7F/4M; mean age 58 years, range 41-78). Presenting symptoms included hemoptysis (4), cough (3), dyspnea (1), stridor (1), and shoulder pain (1). Most had a tracheal mass (5), while 3 had mainstem bronchi masses and 3 had lung masses. Radiographically, the masses were lobulated, rounded, or polypoid in six patients. All underwent TBNA with a 21- or 22-gauge needle and endobronchial biopsy. The most frequent diagnosis was adenoid cystic carcinoma (4/11, 36%), followed by mucoepidermoid carcinoma (3/11, 27%), epithelial-myoepithelial carcinoma (2/11, 18%), oncocytoma (1/11, 9%), and hyalinizing clear cell carcinoma, salivary gland type (1/11, 9%). The surgical pathology specimens confirmed the diagnosis in all cases. CONCLUSIONS To our knowledge, this is one of the largest cytomorphologic studies of primary salivary gland tumors of the tracheobronchial tree in the literature. Salivary gland tumors of the tracheobronchial tree are rare, and recognizing cytomorphologic changes that occur in salivary gland-type tumors is important for establishing a definitive diagnosis.

Context.—Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers.Objective.—To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities.Data Sources.—This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature.Conclusions.—Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

ObjectiveWe sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma).MethodsFifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis).ResultsaSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (pConclusionCD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.

Objectives Cryptococcal meningoencephalitis is the most common fungal infection of the central nervous system diagnosed by cerebrospinal fluid cytology (CSF) studies. Existing literature suggests that routine CSF cytomorphologic evaluations are exquisitely specific; however, less is known about their sensitivity. Methods An electronic record review of the cytopathology and microbiology files was conducted for the 21-year interval from January 1, 1995, through December 31, 2015. Results In 21 years, 12,584 CSF samples were processed in the laboratory. Of these, 24 (0.2%) were reported positive for cryptococcal organisms by light microscopy, and 129 CSF fungal cultures were positive for Cryptococcus species. All cotested specimens with positive cytology results were positive on culture (15 specimens, 100% specificity). Twenty-four samples with positive culture results were negative by CSF cytology (sensitivity 39%). Conclusions When culture is used as a gold standard, CSF cytology is 100% specific and 39% sensitive, with a positive predictive value of 100% and a negative predictive value of 99.8%.

Background Surgeons often rely on intra-operative histology (frozen sections [FS]) to determine the next step in surgical management during the second stage (re-implantation surgery) of 2-stage revision arthroplasty. The purpose of the study is to assess the accuracy of permanent sections (PS) and FS in the diagnosis of persistent infection during re-implantation in patients with an inflammatory arthritis. Methods From 2001 to 2016, 47 planned second-stage revision total hip arthroplasty and total knee arthroplasty in patients with inflammatory arthritis were identified. Revisions were classified as having persistent infection if they were Musculoskeletal Infection Society positive at the time of second stage. PS or FS was considered to be positive for infection when at least one of the specimens demonstrated an acute inflammation. Receiver operating characteristic analysis was performed to obtain the diagnostic parameters. Results There were 9 (19%) persistent infections. Both PS and FS had very high specificity (PS = FS = 94.7%). Sensitivity of PS was higher than FS, although not statistically significant (PS = 88.9%, FS = 55.6%, P = .083). Overall, PS had a better diagnostic utility than FS (area under the curve: PS vs FS = 0.92 vs 0.75, P = .045). Four specimens had discrepancies between PS and FS histology. In all 4 instances, the specimens were read as positive (infected) by PS, but negative by FS. Conclusion Histological analysis is recommended at the time of re-implantation surgery even in patients with inflammatory arthritis. PS had a better diagnostic utility than FS suggesting that areas of acute inflammation may be scattered and may not always be captured in the specimens taken for FS.

Background Several previous studies have described broad histologic classifications of peri-prosthetic reactions that likely reflect the underlying mechanism of arthroplasty failure; however, a consensus has not yet been reached about the relative importance of individual observations. Question/Purpose The purpose of this study was to evaluate the inter-examiner repeatability of commonly used histopathologic grading methods, and to determine the utility of assigning a more simple, global categorization in patients undergoing revision THA surgery of implants with a variety of bearing combinations. Methods Between March 2013 and February 2020, a total of 2131 patients underwent revision hip arthroplasty surgery at a one center, of which 12% (248 of 2131) of patients were enrolled. Two pathologists independently reviewed microscope slides of periprosthetic tissue from these patients, of which 425 slides (229 hips, 222 subjects) were reviewed by both pathologists. Separate slides were used for a priori training of the pathologists. Slides were evaluated with the Campbell Aseptic Lymphocyte-dominant Vasculitis-Associated Lesion (ALVAL) score, the Oxford ALVAL score as modified by Grammatopolous, the Fujishiro and Natu scores, and a proposed simplified pattern classification, similar to that of Krenn et al., that incorporates individual factors of these existing scoring methods and was previously shown to correspond to Magnetic Resonance Imaging findings. Inter-rater agreement was assessed using Gwet’s AC1 and AC2 coefficients and correspondence analysis was used to examine associations between individual factors of prior scoring methods with the proposed major pattern. Results Almost perfect inter-rater repeatability (Gwet’s AC2 > 0.8) was found for 71% (15/21) of the individual factors, and substantial interrater agreement was found for the proposed major overall pattern (Gwet’s AC1: 0.80, 95%CI: 0.72–0.85). Correspondence analysis was able to explain 89–91% of data variability and was able to identify individual features not commonly associated with a major pattern, but discriminatory of the major pattern, such as “Lymph Cuff Thickness 0.25–0.5″ with ALVAL. Conclusion In contrast to prior examinations, excellent interrater agreement was found that may be attributable to a priori training of raters with a test set of slides or difficulty of interpreting grading criteria. The proposed simplified major pattern classification may facilitate evaluation of histopathologic tissue samples.

Background and Aims Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells. Methods We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS. Results One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure. Conclusion Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.)

Bone-forming tumors are defined by neoplastic cells that differentiate along the lines of osteoblasts that deposit neoplastic bone. The morphology and biological spectrum of bone-forming tumors is broad, and their accurate diagnosis requires the careful correlation of their clinical, morphologic, and radiologic characteristics. Immunohistochemical and molecular analyses have an important role in select instances. At present, the identification of neoplastic bone largely depends on histologic analysis, which can be subjective. The major types of osteosarcoma are defined according to their morphology, origin within or on the surface of the bone, and their histologic grade.

Hemangioma of the bone is a benign neoplasm of endothelial cells that form blood vessels. It is one of the most common tumors of bone and has been found in vertebral bodies in approximately 10% of the adult population. The lesions can be classified according to their morphology and number. They include conventional capillary or cavernous hemangioma, diffuse cystic angiomatosis, and hemangioma/lymphangioma with massive osteolysis (Gorham-Stout syndrome, aka disappearing bone disease). Conventional hemangioma is often asymptomatic and is more frequent in adult women. Vertebral bodies are the most common location, followed by the craniofacial bones and metaphyses of long bones. Imaging of hemangioma is characterized by coarse trabeculations. Asymptomatic lesions may not require treatment. Prognosis is excellent.

Vascular tumors of the joint are rare; they are defined as neoplastic proliferations of cells with endothelial phenotype that arise in periarticular structures, especially the synovium. The majority of cases reported in the literature are synovial hemangiomas. The knee joint is the most common location. Angiosarcoma of the joint is extremely rare. Clinically, intra-articular hemangioma can cause pain, tenderness, swelling, and hemarthrosis. Phleboliths can be identified on plain radiographs. MRI shows an intra-articular or juxta-articular soft tissue mass of intermediate signal intensity on T1-weighted images and of high signal intensity of T2-weighted images. Microscopically, the tumors can be composed of capillary, cavernous, or mixed arteriovenous types. Current treatment is surgical excision via arthroscopy, or open excision if the lesion is diffuse. Preoperative embolization may be effective for diffuse lesions.

Preoperative diagnosis of soft tissue and bone tumors using needle biopsy techniques, namely fine needle aspiration (FNA) and core needle biopsy (CNB), has gained wider acceptance in recent years. This is achieved in concert with the maturation of various image-guided needle biopsy techniques, development of molecular genetic diagnostics, and expansion of immunohistochemical biomarkers. FNA, however, as a first-line approach to evaluate soft tissue and bone tumors, remains one of the most challenging and controversial areas in cytopathology. Compared with the CNB, FNA is more suitable for smaller lesions, recurrent and/or metastatic tumors, and lesions with a broad differential diagnosis including carcinomas and lymphomas. Enhanced by rapid on-site evaluation (ROSE), and immediate tissue triage for flow cytometry and/or cytogenetic/molecular studies, FNA offers a valuable and fast diagnostic modality for lesions suspicious for high grade malignancy. This chapter focuses on the practical approaches to this extremely diverse set of benign and malignant neoplasms, emphasizing on pattern recognition, effective triage of biopsy material, and judicious use of ancillary studies. General discussion of the clinical and cytomorphologic features of each entity is beyond the scope of this diagnostic approach–orientated chapter, and the readers are directed to other relevant excellent textbooks.

History A 92-year-old bedridden woman presented to the emergency department from an assisted living facility with fever, cough, and swelling over the right lateral hip. She had baseline dementia and frailty and had been bedridden for 4 years. She did not have any recent falls or history of trauma at the site of swelling. She had a history of diffuse large B-cell lymphoma that had been diagnosed and treated 7 years ago, and thoracoabdominal CT at last follow-up 3 years ago did not show any recurrence. Physical examination findings were unremarkable except for a painful hard and fixed mass measuring approximately 5 × 5 × 10 cm (in the transverse, anteroposterior, and craniocaudal directions, respectively) located at the right lateral superior thigh. The overlying skin was intact, without any color changes. Pertinent blood test results showed an increased white blood cell count of 13 000/μL (13 ×10

Introduction Polyomavirus cytopathic effect (BK-CPE) is classified as “negative for high-grade urothelial carcinoma” (NHGUC) in the Paris System for Reporting Urinary Cytology. However, polyomaviruses have been historically associated with tumor development and have been recently reported as an independent risk factor for renourinary carcinoma in transplant patients. The aim of the present study was to investigate the relationship between polyomavirus infection in the urinary tract and the subsequent risk of developing high-grade urothelial carcinoma (HGUC) in the general population. Materials and methods: A retrospective case-control study was conducted to assess BK-CPE in all urinary cytology examinations performed from 2009 to 2011 for cases with an interpretation of NHGUC, NHGUC with BK, atypical urothelial cells (AUCs), or AUCs with BK. The endpoint of the present study was a diagnosis of HGUC on either bladder biopsy or urine cytology for those patients with subsequent follow-up data. Results A total of 252 cases with a urinary cytology interpretation of NHGUC, 234 with NHGUC + BK, 255 with AUCs, and 64 with AUCs + BK were identified. The surgical and cytological follow-up data showed that the overall risk of the development of HGUC for those with NHGUC, NHGUC + BK, AUCs, and AUCs + BK was 6.0%, 6.8%, 23.5%, and 12.5%, respectively. No statistically significant differences were found between the patients with NHGUC and those with NHGUC + BK. A statistically significant difference was found for patients with AUCs compared with patients with NHGUC + BK and those with AUCs + BK (P Conclusions The presence of BK-CPE in urine cytology samples does not increase the overall risk of the development of HGUC. Our results support the recommendation from the Paris System for Reporting Urinary Cytology to place urine samples with BK-CPE in the NHGUC category.

Polyomavirus-associated nephropathy (PVAN) is one of the most common disease affecting transplant patients, mainly caused by BK polyomavirus (BKV) and with5% of the cases caused by JC polyomavirus (JCV). Screening and early intervention, including appropriate reduction in immunosuppressive therapy, are critical to reduce allograft loss. The presence of decoy cells in the urine is a characteristic cytopathic effect of polyomavirus. The goal of this study was to investigate the significance of decoy cells in urine cytology in transplant patients, comparing with the plasma viral replication level detected by the real-time quantitative BK virus polymerase chain reaction test (Qt-BK PCR).A cohort of post-transplantation patients with serum BKV level monitored by Qt-BK PCR from 2008 to 2013 was studied. Among them, 35 patients had both urine cytology (UC) analysis and Qt-BK PCR performed. The clinical presentation along with the available UC slides were retrieved and reviewed.Compared with Qt-BK PCR, the sensitivity, specificity, positive predictive value, and negative predictive value of urine cytology analyzed within one week apart were 92%, 71%, 85%, and 83%, respectively. The accuracy of the UC was 84%. More interestingly, UC played a key role in identifying a case of JCV associated PVAN whereas Qt-BK PCR from both urine and plasma failed to detect this virus.Our data suggests that urine cytology is a sensitive surveillance test for early detection of polyomavirus in transplant patients, and it is particularly useful to screen for rare JC polyomavirus.

Sarcoidosis is a systemic inflammatory disorder characterized by non-caseating granulomas, predominantly involving lung, mediastinal lymph nodes and other organs. Synovium involvement is infrequent, and as far as we know, involvement of a periprosthetic membrane has not been reported in the English literature. Intra-articular diffuse tenosynovial giant cell tumor ("conventional diffuse pigmented villonodular synovitis") is an uncommon, locally aggressive neoplasm with few previous case reports in which it arose in periprosthetic tissues after knee arthroplasty. We describe a unique case of an intraarticular mass next to a total knee prosthesis implanted 6 years ago in a patient with a history of pulmonary sarcoidosis. Clinically, this 67-year-old gentleman presented with progressive left knee pain, effusion and marked instability. MRI showed a large complex effusion with synovial thickening in the supra patella recess and the medial and lateral gutters. In addition, a large multilobulated mass with mixed low and high signal intensity was present in the posterior joint space, extending into the popliteal area. A two-stage operation was performed. Histologically, the mass from the posterior joint space showed characteristic features of diffuse tenosynovial giant cell tumor, while the synovium from the anterior compartment demonstrated sarcoidal granulomatous inflammation. Orthopaedic wear debris was found within the giant cells of these sarcoidal granulomata. The histologic features are different from those "usual" macrophage reactions to the particles of debris. In this article, we also included two optional links (highlighted in blue in the figures) to digital whole slide image (WSI), which allow the readers to navigate the entire microscope slides.

Total joint arthroplasty is one of the most successful of all operations, but arthroplasty failures do occur. By evaluating the retrieved devices and periprosthetic tissues, pathologists can often recognize clues about the mechanism of arthroplasty failure, information that can be of value to treating physicians, manufacturers and regulatory bodies. In this review, we provide an overview of the history of joint replacement implant development, describe the most common mechanisms of arthroplasty failure, and illustrate the types of damage that can be recognized during gross evaluation of retrieved devices. We emphasize the histologic findings in periprosthetic tissues, especially features typical of infection or other adverse local tissue reactions. We also summarize the histology of bone grafts and graft substitute materials in biopsy and resection specimens, which can help explain unexpected histologic findings at sites of prior reconstructive orthopaedic surgery, and can contribute to the development of new materials.

Background Despite mixed results in the literature, some clinicians continue to consider an elevated CD4/CD8 ratio in bronchoalveolar lavage (BAL) fluid to be supportive of a diagnosis of sarcoidosis. However, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoidosis has not been extensively studied. The primary aim of this study was to evaluate the utility of the CD4/CD8 ratio in mediastinal lymph node aspirates obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing sarcoidosis. Methods Our archives were searched for EBUS-TBNAs in which mediastinal lymph node aspirates had been submitted for flow cytometry (n=160). Clinical and pathologic findings in these cases were reviewed retrospectively. Cases were included in the study if they had (1) a clinical diagnosis of sarcoidosis supported by cytopathologic confirmation of non-necrotizing granulomas in EBUS-TBNA-derived lymph node aspirates (23 cases), or (2) a pathologically confirmed non-neoplastic diagnosis other than sarcoidosis (7 cases). Cases that did not fulfil these criteria were excluded (130 cases). Results The CD4/CD8 ratios in mediastinal lymph nodes and BAL fluid were compared. The CD4/CD8 ratio was elevated in mediastinal lymph nodes in 12/23 (52%) cases of sarcoidosis and 3/7 (43%) pathologically confirmed nonsarcoid cases. BAL fluid had been concurrently submitted for flow cytometry in 20/23 cases of sarcoidosis and 5/7 nonsarcoid cases. CD4/CD8 was elevated in BAL fluid in 9/20 (45%) cases of sarcoidosis and 2/5 (40%) nonsarcoid cases. Conclusion As in BAL fluid, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoid granulomas is highly variable and does not reliably confirm or exclude sarcoidosis.

Background & Aims Microsatellite instability (MSI) in colorectal cancer cells results from deficient mismatch repair (MMR) protein function, either acquired or from germline alterations such as in patients with Lynch syndrome. Universal screening initiatives for Lynch syndrome have been encouraged. However, little is known about the true prevalence of MMR deficiency and MSI in colorectal tumors among individuals from different racial and ethnic subgroups or their clinical effects in these populations. Methods We performed a retrospective analysis of 253 surgically resected, primary colorectal adenocarcinoma specimens identified from the University of Miami tumor registry from 2005 through 2010. We collected clinical data, including overall survival (OS), the proportion of patients alive at specific intervals, from non-Hispanic white, Hispanic, and black patients matched by stage. We performed immunohistochemical staining to detect MMR proteins in all specimens and polymerase chain reaction analysis of 51 tumors to detect MSI. Results We detected MMR deficiency in 28 of 253 cases (11.1%), evenly distributed among blacks (9.6%), non-Hispanic whites (10.4%), and Hispanics (12.6%) ( P = .79). Combined deficiencies in MLH1 and PMS2 were found in 23 of 28 MMR-deficient samples (82.1%); MSH2 and MSH6 were most frequently absent in tumor samples from Hispanics ( P = .03). Eleven of 51 tumor samples (21.6%) had high levels of MSI, and we observed a high level of concordance between MMR and MSI (κ = .81). OS was significantly better in patients whose tumors had deficient MMR (hazard ratio for patients with MMR-deficient tumors vs MMR proteins intact = 0.37; 95% confidence interval, 0.15–0.91; P = .03). Race and ethnicity were not significant predictors of OS. Conclusions MMR deficiency in colorectal tumors occurs with similar rates among patients of different racial and ethnic groups, which is based on immunohistochemical analysis of 253 primary tumor specimens. This finding indicates the potential value of universal testing of colorectal cancer by immunohistochemistry in minority populations and confirms the benefit of MMR deficiency to OS.

Cryptococcal meningoencephalitis is the most common fungal infection of the central nervous system diagnosed by cerebrospinal fluid cytology (CSF) studies. Existing literature suggests that routine CSF cytomorphologic evaluations are exquisitely specific; however, less is known about their sensitivity.An electronic record review of the cytopathology and microbiology files was conducted for the 21-year interval from January 1, 1995, through December 31, 2015.In 21 years, 12,584 CSF samples were processed in the laboratory. Of these, 24 (0.2%) were reported positive for cryptococcal organisms by light microscopy, and 129 CSF fungal cultures were positive for Cryptococcus species. All cotested specimens with positive cytology results were positive on culture (15 specimens, 100% specificity). Twenty-four samples with positive culture results were negative by CSF cytology (sensitivity 39%).When culture is used as a gold standard, CSF cytology is 100% specific and 39% sensitive, with a positive predictive value of 100% and a negative predictive value of 99.8%.

Context.— Given the increasing demand for molecular testing of non–small cell lung carcinoma specimens to guide therapeutic decision-making and the trend toward minimally invasive techniques for obtaining diagnostic tissue, cytopathology laboratories must devise strategies to maximize DNA yield for necessary molecular testing. Objective.— To describe our experience at Cleveland Clinic with epidermal growth factor receptor (EGFR) mutation testing by next-generation sequencing and anaplastic lymphoma kinase (ALK) gene rearrangement testing by fluorescence in situ hybridization of non–small cell lung carcinomas diagnosed by cytology, with an emphasis on specimens obtained by endobronchial ultrasound–guided transbronchial fine-needle aspiration. Data Sources.— Data sources include a review of the current literature, including published articles from our institution. Conclusions.— At our institution, liquid-based cytology specimens are the primary resource used for molecular testing of non–small cell lung carcinomas; in most instances, adequate DNA can be extracted from the residual cell pellet for next-generation sequencing, and ThinPrep slides can be used reliably for fluorescence in situ hybridization testing for ALK gene rearrangements. In occasional cases where the cell pellet material is not adequate for molecular testing, cell blocks and/or surgical pathology specimens are secondary options. The cytopathologist's role in specimen handling and triage is essential to ensure that molecular testing can be carried out successfully.

Angiomyolipoma (AML) arises primarily from the kidney but may grow into the retroperitoneal space mimicking a primary retroperitoneal tumor. Fine needle aspiration (FNA) and core needle biopsy of AML, particularly the fat-predominant variant, may be difficult to distinguish from retroperitoneal well-differentiated liposarcoma (WDLS) or lipoma. Commonly used immunomarkers, MDM2 and p16, have proven useful in diagnosing WDLS and dedifferentiated liposarcoma (DDLS), while HMB45 and Melan-A are melanocyte-related markers characteristically expressed in AML. In this study, we investigated the utility of MDM2 and p16 along with HMB45 and Melan-A immunohistochemical analysis in distinguishing AML from WDL/DDLS or lipoma. Immunohistochemically, AMLs demonstrated focal MDM2 expression (40% of cases) and focal/diffuse expression of p16 (60%). AMLs marked focally or diffusely with HMB45 (76% of cases) and Melan-A (96%). These latter two immunomarkers were not expressed in any of the WDLS/DDLSs or lipomas tested. WDLS/DDLSs showed focal/diffuse expression of MDM2 (91% of cases) and p16 (97%). While focal expression of MDM2 and p16 was observed in 14% and 67% of lipomas, respectively, no lipoma exhibited diffuse MDM2 positivity. In our hands, MDM2 expression by itself cannot exclude the diagnosis of AML or lipoma, and p16 alone is not helpful in separating AML and conventional lipoma from WDLS/DDLS. However, along with morphology, an immunohistochemical battery including HMB45, Melan-A, MDM2 and p16 are useful in distinguishing AML from WDLS/DDLS or lipoma. For equivocal cases, fluorescence in situ hybridization for MDM2 should be performed.

Management of soft tissue sarcomas is often complicated, requiring radiation before and in some cases after limb-sparing surgery. Radiation necrosis is a severe complication after radiation treatment and is typically dose related and involves medullary bone. We report on two cases of hitherto unreported focal circumscribed intra-cortical lytic lesions within the radiation portal, which appeared 19 months and 31 months, respectively, after the conclusion of radiation treatment. Both patients had a history of soft tissue sarcoma treated with radiation (66 Gy) and surgical resection. Biopsy of these lesions showed necrotic bone attributed to radiation.

Cartilaginous neoplasms of soft tissue and synovium are relatively uncommon. The vast majority is benign and the neoplastic matrix is usually hyaline in type. The heterogeneity in their histologic features, especially the degree of cellularity and cytological atypia may pose challenges in diagnosis. Immunohistochemistry and molecular analyses are helpful in only specific circumstances stressing the importance of accurate histologic interpretation.

β-catenin immunohistochemical stain can be useful in the diagnosis of many tumors including desmoid-type fibromatosis (DTF). Lymphoid enhancer-factor 1 (LEF1), a recently emerged marker, is part of the Wnt pathway with β-catenin but has not been studied in DTF. We performed LEF1 and β-catenin immunohistochemistry in DTF (n=26), superficial fibromatosis (n=19), sclerosing mesenteritis (n=12), gastrointestinal stromal tumor (n=17), and cutaneous scar (n=14) using tissue microarray and whole sections. The staining intensity was scored as strong (visible at ×2 objective, value of 3), moderate (visible at ×4, value of 2), weak (visible at ×10, value of 1), and negative (not visible at ×10, value of 0). The percentage of positive nuclei was recorded in 10% increment. Histologic scores were generated by multiplying numerical value of intensity and percentage of positive nuclei. A score of at least 10 was defined as positive. Eighteen of the 25 DTF were positive for LEF1 while 12 of 25 were positive for β-catenin (1 excluded due to loss of tissue). Gastrointestinal stromal tumor cases were negative for both markers. All superficial fibromatoses were negative except 2 cases with weak positivity for LEF1 but not β-catenin. Only 2 case of sclerosing mesenteritis were weakly positive for LEF1 but negative for β-catenin. Ten of 14 scars were positive for LEF1 but only 1 of them was weakly positive for β-catenin. In conclusion, this study demonstrated that LEF1 may be a useful marker in the differential diagnosis of DTF in certain contexts. However, caution should be exercised since LEF1 positivity can also be seen in scars.

The endocrine system is an embryological diverse system consisted of a variety of glands, such as pituitary, parathyroid, thyroid, adrenal, endocrine pancreas, and the diffuse neuroendocrine system. Endocrine tumor can be presented as a sporadic event, or as part of an inherited tumor syndrome. During the past century, inherited tumor syndromes have emerged as an important group of diseases. With the growing knowledge of each inherited tumor syndrome in the molecular genetic level, many changes in clinical management have occurred. This review focuses on the endocrine tumors involving the pituitary, parathyroid, thyroid, adrenal, and endocrine pancreas, in the setting of inherited tumor syndromes. We discuss the specific clinical, molecular genetic, and pathologic features of endocrine tumor in each gland and their associated inherited tumor syndromes. By understanding the pathogenesis of inherited endocrine tumor syndromes and recognizing the unique features of pathologic findings, pathologists bear the responsibility to provide the clinicians the guidelines in terms of screening and treatment of inherited tumor syndromes.

Solid organ transplant–associated graft-versus-host disease is an infrequent and potentially lethal complication. The incidence of this complication varies according to the type of organ transplant with higher rates associated with liver and small bowel transplants. The clinical presentation typically includes fever and skin rash, and most cases quickly advance to become a multisystem disease affecting the bone marrow and other nontransplanted solid organs. The diagnosis is based on the clinical symptoms, pathologic changes in biopsied tissues, and systemic lymphoid chimerism. The mortality of this disease can exceed 75% after liver transplant and most patients die from infections or hemorrhage due to bone marrow failure. There is no standard treatment strategy for this complication, and the management mainly consists of both prophylaxis and immediate treatment without delay. This short review summarizes the current pathogenesis, diagnosis, and treatment of this entity.

Lesions that contain abundant benign myoepithelial cells, including pleomorphic adenomas of salivary gland origin, may present a diagnostic challenge in fine-needle aspiration (FNA) specimens. Benign metastasizing pleomorphic adenoma is a rare neoplasm, in which the benign appearing pleomorphic adenoma, without any histological evidence of malignancy, metastasizes to distant sites including lung. In the absence of clinical history of a pre-existing myoepithelial neoplasm, the presence of myoepithelial cells in the lung or any other organs besides salivary glands may create diagnostic difficulty. Here we present the cytologic findings of such a metastatic tumor found in the lung FNA and pleural fluid specimens from a 64-year-old woman, with a history of local recurrent salivary gland pleomorphic adenomas, who presented with multiple bilateral pulmonary nodules and pleural effusion. The diagnosis of benign metastasizing pleomorphic adenoma was made based on clinical information and cytomorphology, and confirmed by immunocytochemistry.

Pseudomyogenic hemangioendothelioma (PMH) is a well-recognized neoplasm that usually arises in the soft tissue; concurrent bone involvement occurs in 24% of cases. PMH of bone without soft tissue involvement is rare. We describe the clinicopathologic findings of 10 such cases, the largest series reported to date. The study included 9 male and 1 female patient; their ages ranged from 12 to 74 years (mean 36.7 y). All patients had multiple tumors with a distinct regional distribution: 45% restricted to the lower extremity; 25% to the spine and pelvis; and 15% to the upper extremity. On imaging studies the tumors were well circumscribed and lytic. The neoplasms were composed of spindled cells arranged in intersecting fascicles with scattered epithelioid cells; epithelioid cells predominated in 3 cases. The neoplastic cells contained abundant densely eosinophilic cytoplasm and vesicular nuclei. There was limited cytologic atypia and necrosis, few mitoses (0 to 2/10 high-power fields), and inconspicuous stroma. Unique findings included abundant intratumoral reactive woven bone and hemorrhage with numerous osteoclast-like giant cells. Immunohistochemically, most tumors were positive for keratin, ERG, and CD31; CD34 was negative. The balanced t(7:19)(q22;13) translocation was documented in 3 cases. Follow-up is limited, but no patient developed documented visceral dissemination, and all have stable or progressive osseous disease. PMH exclusively involving bone is rare. It is multicentric, often involves the lower extremity, and has unusual morphology. The differential diagnosis includes epithelioid vascular neoplasms, giant cell tumor, bone forming neoplasms, and metastatic carcinoma. Because of its rarity, unusual presentation, and morphology, accurate diagnosis can be challenging.

Background The current gold standard to diagnose periprosthetic joint infection (PJI)—the Musculoskeletal Infection Society (MSIS) criteria, requires a battery of tests, the results of which may not be available at the time of decision-making. Thus, surgeons often rely on intraoperative frozen section histology. However, the accuracy of frozen sections has not been determined when matched for the MSIS criteria. We aimed to (1) assess the value of intraoperative histology in the diagnosis of PJI and (2) evaluate discrepancy rate between frozen and permanent section analysis. Methods A retrospective review of patients who underwent revision total hip or total knee arthroplasty for either PJI or mechanical failure in 2013 was conducted. Two hundred procedures where tissue samples for frozen sections had been collected were identified and included into the study. Results of frozen sections were compared to the modified MSIS criteria. Discrepancy rate between frozen and permanent sections was also calculated. Results Frozen sections had sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 73.7% (95% confidence interval [CI], 59.7%-87.7%), 98.8% (95% CI, 97.1%-100.0%), 94.1% (95% CI, 90.6%-97.6%), 93.3.4% (95% CI, 84.4%-100.0%), 94.0% (95% CI, 90.7%-97.3%), respectively. There were 10 discrepancies between the results of frozen and permanent sections (N = 421 samples), thereby yielding 97.6% concordance. Conclusion When matched to the MSIS criteria, intraoperative frozen section histology yields a high specificity, positive predictive value, negative predictive value, accuracy, and moderate sensitivity. The discrepancy rate between frozen and permanent sections is low and both demonstrate good approximation of MSIS criteria.

Bone and soft tissue tumors encompass a remarkably diverse spectrum of benign and malignant entities. Over the last couple decades, molecular genetic abnormalities have demonstrated to be an important, sometimes necessary adjunct for diagnosis, prognostication, and therapeutics of bone and soft tissue tumors. In general, bone and soft tissue tumors can be classified broadly into two groups: those neoplasms with complex, nonspecific cytogenetic profiles (Table 12.1) and those with relatively simple, consistent, and recurrent cytogenetic and molecular aberrations (Tables 12.2 and 12.3). The methods used to detect those molecular genetic aberrations include fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) array, polymerase chain reaction, and sequencing. Those tests are frequently performed on formalin-fixed, paraffin-embedded (FFPE) tissues in the clinical laboratories. However, with the popularity of new technologies such as interventional radiology and ultrasound-guided fine needle aspiration, clinicians often request that specific molecular genetic tests be performed on the limited material. It is feasible to have some molecular tests done on cytology specimens, such as touch prep, thin-prep, cell block, or fluid. Some tests are actually more easily performed on cytology specimens and can provide much better results (such as FISH performed on thin-prep slide). This chapter is divided into two major sections: (1) summary of recurrent or tumor-specific genetic events in bone and soft tissue tumors, and (2) overview of the molecular approaches commonly used in clinical practice. A brief discussion of some molecular tests for bone and soft tumor performed on cytology samples is also provided.

Intracellular Mg2+ and natural polyamines block outward currents in BK channels in a highly voltage-dependent manner. Here we investigate the contribution of the ring of eight negatively charged residues (4 x E321/E324) at the entrance to the inner vestibule of BK channels to this block. Channels with or without (E321N/E324N) the ring of negative charge were expressed in oocytes and unitary currents were recorded from inside-out patches over a range of intracellular Mg2+ and polyamine concentrations. Removing the ring of charge greatly decreased the block, increasing KBap (0 mV) for Mg2+ block from 48.3 ± 3.0 to 143 ± 8 mM, and for spermine block from 8.0 ± 1.0 to 721 ± 9 mM (150 mM symmetrical KCl). Polyamines with fewer amine groups blocked less: putrescine < spermidine < spermine. An equation that combined an empirical Hill function for block together with a Boltzmann function for the voltage dependence of KBap described the voltage and concentration dependence of the block for channels with and without the ring of charge. The Hill coefficients for these descriptions were

Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma.

We report a unique case of an extramammary mammary-type myofibroblastoma of the perianal region. The patient was a 40-year old female with no significant past history, who presented with a right side painless perianal mass. Gross examination of the excised mass showed a well-circumscribed, apparently encapsulated, nodular mass weighing 30 g and measuring 5 cm. in the greatest dimension. The cut surface showed solid, yellow homogenous tissue. Microscopically, the neoplasm was composed of bland spindled cells generally arranged into short fascicles with abundant myxoid stroma. The cells stained strongly for desmin and CD34. To our knowledge, a review of the literature discloses only ten cases of extramammary, mammary-type myofibroblastoma.

Dedifferentiated chondrosarcoma is a primary bone tumor characterized by the presence of both low-grade cartilaginous and high-grade malignant noncartilaginous components. The high-grade noncartilaginous component is typically a pleomorphic fibroblastic spindle cell sarcoma. Dedifferentiation into a malignant epithelial component is extremely rare. In this report, we present a 74-year-old woman who developed a metastatic squamous cell carcinoma in the right inguinal area 1 year after wide resection of her right proximal femur for a dedifferentiated chondrosarcoma. The dedifferentiated component was composed of poorly differentiated epithelioid cells with foci of squamous cell carcinoma. Mutational analysis was performed, and the isocitrate dehydrogenase 1 R132C mutation was detected in the low-grade chondrosarcoma, dedifferentiated chondrosarcoma as well as the metastatic squamous cell carcinoma. And this mutation was not detected in patient's normal tissue. Our study supports the theory that both the chondrosarcoma cells and dedifferentiated epithelioid tumor cells arose from the same clonal origin.