Tropheryma whipplei Endocarditis Presenting as Valvulopathy and Multiple Septic Emboli.

A 63-year-old man was admitted to the hospital for nausea, vomiting, and right flank pain. He was found to have septic emboli in multiple organs secondary to aortic valve endocarditis. He was started on broad-spectrum antibiotics and underwent valve replacement. Blood cultures from admission were negative, but a blood polymerase chain reaction (PCR) test for fastidious difficult-to-culture pathogens showed a positive result for Tropheryma whipplei. Valve histopathological evaluation confirmed Tropheryma whipplei endocarditis. He was treated with intravenous penicillin followed by oral trimethoprim-sulfamethoxazole. A high index of suspicion for causes of culture-negative endocarditis needs to be maintained when blood cultures are negative despite clear evidence of endocarditis especially with large vegetation sizes and other complications such as septic emboli. Multiple imaging modalities are available to assist with diagnosis including transthoracic and transesophageal echocardiogram as well as cardiac computed tomography. A blood PCR test can identify the implicated pathogen in a more expeditious manner compared to valve histopathological evaluation. Treatment is complex and usually requires surgical intervention and prolonged antimicrobial therapy.

Development and evaluation of an online integrative histology module: simple design, low-cost, and improves pathology self-efficacy.

Integration of core concepts is an important aspect of medical curriculum enhancement. Challenges to improving integration include the risk of curtailing the basic sciences in the process and the push to decrease contact hours in medical curricula. Self-paced learning tools can be developed that deliberately relate basic and clinical sciences to aid students in making interdisciplinary connections. The purpose of this project was to develop, implement, and evaluate a self-paced learning module that would be applicable to integration of different disciplines in medical education. The module was intended to improve integration between histology and anatomic pathology before a respiratory pathology laboratory session. Qualtrics XM, a survey software commonly available at educational institutions, was used in a novel manner to create the module. Module activities included pre- and post-module quizzes; four short videos emphasizing normal histological features and recalling associated pathologies; three categorization activities designed for students to recognize normal versus abnormal characteristics of lung specimens; and post-activity feedback. Preliminary data from first-year medical students showed that post-module quiz scores were significantly higher than pre-module quiz scores (p < 0.001) and that module users' pre-laboratory pathology self-efficacy was significantly higher than non-users (p < 0.05). These data suggest that module use facilitated short-term knowledge gain and improved pathology self-efficacy before the laboratory session. Online modules can be developed affordably using Qualtrics XM to integrate anatomical sciences with other disciplines, while providing students interactive learning resources without increasing contact hours. The module presented in this report focused on normal versus abnormal morphology, guiding students through recognizing the continuum from healthy to disease states before learning about the pathologies more in depth. A similar module design would likely be effective in integrating other disciplines in medicine, especially in disciplines that require recognition of changes in morphology.

Fluorescence in situ hybridization analysis on cytologic smears: An accurate and efficient method in the diagnosis of melanotic Xp11 translocation renal cancer.

Melanotic Xp11 translocation renal cancer is a rare category of MiTF/TFE3 neoplasms morphologically resembling Xp11 translocation renal cell carcinoma, Xp11 translocation perivascular epithelioid cell tumor, and melanoma. The diagnosis requires demonstration of TFE3 gene rearrangement, by either fluorescence in situ hybridization (FISH) at the Xp11.2 locus or by TFE3 immunohistochemistry. As cytology smears can be useful adjuncts in cytogenetic and molecular testing, we demonstrate TFE3 rearrangement by FISH analysis on cytologic smears in melanotic Xp11 translocation renal cancer. An 18-year-old girl presented with a large right renal mass. Intraoperative scrape smears were performed on suspicious aortocaval lymph nodes. A subset of smears was stained (Papanicolaou and DiffQuik). Morphologically, the neoplastic cells exhibited abundant clear vacuolated cytoplasm and moderate to marked nuclear pleomorphism. Unstained and destained smears were examined for TFE3 rearrangement by FISH. Positive TFE3 FISH results on formalin-fixed paraffin-embedded tissue correlated with the positive FISH findings of TFE3 gene rearrangement on cytologic smears. Therefore, the diagnosis of melanotic Xp11 translocation renal cancer was rendered. In Xp11 translocation associated neoplasms, FISH analysis on cytologic smears can be an efficient, accurate, and cost-effective method for evaluating TFE3 rearrangement.

Melanotic Xp11 Translocation Renal Cancer Managed With Radical Nephrectomy and IVC Tumor Thrombectomy.

Melanotic Xp11 translocation renal cancer is a rarely observed neoplasm primarily affecting adolescents and young adults. Given the paucity of data describing this malignancy, its natural history and subsequent long-term management are not well understood. We report a case of melanotic Xp11 translocation with tumor thrombus extension managed with radical nephrectomy and inferior vena cava (IVC) tumor thrombectomy. To our knowledge, this is the first case report to describe use of conventional tumor thrombectomy techniques in a patient with melanotic Xp11 translocation renal cancer.

Value of ultrasound guidance in cytopathologist-performed fine-needle aspirations of palpable lesions.

INTRODUCTION: Fine-needle aspirations (FNAs) of palpable masses are often performed by cytopathologists without ultrasound (US) guidance. Nonetheless, variations in the actual depth of palpable masses lead to occasional challenges. US guidance allows cytopathologists to visualize the mass and guide needle placement. This study retrospectively addressed the utility of US by comparing FNAs performed by cytopathologists on palpable masses with and without US guidance. MATERIALS AND METHODS: Cytopathologist-performed FNAs with and without US guidance from March 1, 2013 to July 1, 2014 were identified. The number of passes, location of lesions, and interpretations were recorded. Available slides were reviewed to determine the proportion of passes that contained diagnostic cellular material and cases in which diagnostic material was present on the first needle pass. RESULTS: In this study, 134 palpation-guided FNAs and 118 US-guided FNAs were analyzed. The percentage of nondiagnostic cases was significantly lower for US-guided FNAs (2.5%) than for palpation-guided FNAs (12.7%; P = 0.004). The average number of needle passes was significantly lower for US-guided FNAs (2.9) than for palpation-guided FNAs (3.6; P = 0.0002). Twenty-two of 118 of US-guided FNAs (18.6%) and 6 of 134 palpation-guided FNAs (4.5%) were completed after only a single pass (P = 0.0008). The percentage of passes with diagnostic material was significantly higher for US-guided FNAs (73.6% versus 60%; P = 0.0002). CONCLUSIONS: For palpable masses, US-guidance adds value to cytopathologists in obtaining diagnostic cellular material more often on the first pass and with fewer passes overall than by palpation alone. This has a potentially beneficial impact on patient care owing to the increased precision and accuracy of needle guidance with ultrasonography.

The utility of PSMA and PSA immunohistochemistry in the cytologic diagnosis of metastatic prostate carcinoma.

The diagnosis of metastatic prostate carcinoma frequently requires the use of immunohistochemical adjuncts. Immunohistochemistry for prostate-specific antigen (PSA) is commonly used for this purpose but can be of limited utility. Recently, prostate-specific membrane antigen (PSMA) has been shown to be a promising marker for the identification of metastatic prostate carcinoma in surgical specimens. The utility of this marker has yet to be reported for cytology specimens. We sought to compare the sensitivities of PSMA and PSA immunohistochemistry and investigate the specificity of PSMA by utilizing cell block preparations from cytologic cases of metastatic prostate carcinoma (n = 19) and carcinomas of nonprostatic origin (n = 33). The sensitivity of PSMA immunohistochemistry was higher (16/19; 84%) in detecting metastatic prostate carcinomas than that of PSA immunohistochemistry (11/19; 58%). Strong, diffuse staining for PSMA was seen in 13 (81%) of 16 PSMA-positive cases whereas strong, diffuse staining for PSA was observed in six (55%) of 11 PSA-positive cases. Positivity for either PSMA or PSA was seen in 17 of 19 cases of metastatic prostate carcinoma for a combined sensitivity of 89%. PSMA immunohistochemistry was completely negative in 32 of 33 cytology cases of nonprostatic carcinomas. Therefore, the specificity of this marker was 97% in this study. In conclusion, our results indicate that PSMA is a highly sensitive and specific immunomarker for the detection of metastatic prostate carcinoma in cytology specimens.

Internal cardiac defibrillator implant-associated angiosarcoma presenting as suspected implant pouch infection.

Medical implants have been rarely associated with the development of sarcomas. We report, to our knowledge, the first case of a high-grade epithelioid angiosarcoma developing in the capsule of an internal cardiac defibrillator implanted subcutaneously over the abdomen over 20 years ago. Although the internal cardiac defibrillator generator had been exchanged in the intervening years, recently, the patient showed a year-long history of systemic symptoms suspicious for implant infection, necessitating several internal cardiac defibrillator pocket hematoma evacuations, always with negative microbiologic cultures. Final reexploration identified suspicious tissue with excessive bleeding which was biopsied and proven to be angiosarcoma on histologic examination. Subsequent imaging demonstrated precipitous progression to liver and lung metastases. Though rare, foreign-body-related sarcoma should be considered in the differential diagnosis for presentations suggestive of hemorrhagic or infectious sequelae of medical implants; this case broadens the range of medical devices associated with angiosarcoma to include now very commonly used implantable medical devices.

Molecular diagnostics of melanoma fine-needle aspirates: a cytology-histology correlation study.

Patients with advanced-stage melanoma harboring a BRAF mutation are candidates for BRAF inhibition as a therapeutic strategy. The use of fine-needle aspiration (FNA) to diagnose metastatic melanoma is increasing. Studies examining the predictive value of BRAF mutation analysis on melanoma FNAs via correlation with follow-up excision findings are lacking. We examined 37 consecutive FNA cases of metastatic melanoma in which the aspirated lesion was subsequently excised. DNA was purified from Diff-Quik-stained FNA smears and tissue blocks from corresponding excisions in parallel. BRAF mutation status was successfully obtained from both specimen types in 34 (92%) of 37 cases. BRAF mutations were detected in 12 (35%) of 34 cases-11 V600E and 1 V600K. Results of BRAF mutational analysis were concordant in all 34 FNA smear/tissue excision pairs. Thus, melanoma FNA for molecular diagnostics represents a rapid, minimally invasive, and effective management strategy in this era of precision medicine.

Epstein-Barr virus associated smooth muscle tumors. Synchronous liver and lung involvement.

Epstein-Barr virus associated smooth muscle tumors (EBV-SMT) are rare neoplasms that can occur in various anatomical locations. They mainly affect immunocompromised patients, and their clinical presentation is variable depending on size and organ involvement. They can pose diagnostic challenges, therefore if they are not considered in the differential diagnosis, they can be definitely misdiagnosed. Synchronous and multifocal involvement has been reported. Although malignant behavior maybe rarely seen; most behave in a benign fashion with favorable clinical outcome. We herein report an unusual case of synchronous EBV-SMT that occurred in the lung and liver in a 44-year-old female patient 7 years after renal transplantation. Both lesions were histologically examined revealing benign appearing spindle cell neoplasm that was positive on immunohistochemical staining for smooth muscle actin, desmin, and caldesmon with strong nuclear staining for EBV RNA by in situ hybridization. A brief pertinent literature review and discussion of EBV-SMT pathogenesis is offered.

Challenges and opportunities in the application process for fellowship training in pathology: an independent survey of residents and fellows demonstrates limited interest in an NRMP-style matching program.

A survey completed by 366 pathology residents and fellows examined preferences for 3 fellowship application systems: keeping the current system, a National Resident Matching Program (NRMP)-style match, and a unified time line. All groups showed a strong preference for a time line, accounting for 62.1% of first choices vs the current system (17.3%) or a match (20.6%). When asked for a second choice after time line was ranked first, 60.5% of respondents whose fellowship of choice was available at their residency institution and 63.5% who had accepted fellowship positions at their residency institution preferred the current system; 51.4% whose fellowship of choice was not available at their residency institution and 50.6% of those who had accepted fellowship positions elsewhere preferred a match. Location and family/personal reasons were more important than subspecialty competitiveness and program prestige when accepting fellowship positions. Pressure to choose and apply early for fellowship persists and is greatest for anatomic pathology-only and clinical pathology-only residents.

Harmful and protective roles of neutrophils in sepsis.

The current studies demonstrate protective and harmful effects of neutrophils (PMN) during experimental sepsis after cecal ligation and puncture (CLP). It is known that CLP induces signaling defects in blood PMN. When PMN were depleted 12 h after CLP, there were dramatic reductions in levels of bacteremia, evidence for reduced liver and renal dysfunction, sharp reductions in serum levels of cytokines (IL-1beta, IL-6, IL-10, TNF-alpha, and IL-2), and improved survival. In contrast, PMN depletion before CLP resulted in substantial increases in bacteremia and no evidence for attenuation of liver and renal failure dysfunction. These data suggest that at the onset of sepsis, PMN are important in regulating the levels of bacteremia, whereas after the onset of sepsis, as they lose innate immune functions, their presence is associated with higher levels of bacteremia and intensified organ dysfunction.

Relationship of acute lung inflammatory injury to Fas/FasL system.

There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters ((125)I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.

Regulation by C5a of neutrophil activation during sepsis.

In sepsis, there is evidence that excessive C5a generation leads to compromised innate immune functions, being associated with poor outcome. We now report that in vitro exposure of neutrophils to C5a causes increased levels of IkappaBalpha, decreased NF-kappaB-dependent gene transcription of TNFalpha, and decreased lipopolysaccharide (LPS)-induced TNFalpha production. Similar findings were obtained with neutrophils from cecal ligation/puncture (CLP)-induced septic rats. Such changes were reversed by antibody-induced in vivo blockade of C5a. In contrast, in vitro exposure of alveolar macrophages to C5a and LPS resulted in enhanced production of TNFalpha and no increase in IkappaBalpha. These data suggest that CLP-induced sepsis causes a C5a-dependent dysfunction of neutrophils, which is characterized by altered signaling associated with NF-kappaB activation.

Neutrophil C5a receptor and the outcome in a rat model of sepsis.

Complement fragment 5a (C5a)-C5a receptor (C5aR) signaling plays an essential role in neutrophil innate immunity. Blockade of either the ligand or the receptor improves survival rates in experimental sepsis. In the current study, sepsis was induced in rats by cecal ligation/puncture. Early in sepsis C5aR content on neutrophils significantly dropped, reached the nadir at 24 h after onset of sepsis, and progressively elevated thereafter. Western-blot, RT-PCR, and confocal microscopy analyses revealed that the loss and re-expression of C5aR during sepsis might be due, at least in part, to the receptor internalization and reconstitution. The reduction and reconstitution of C5aR correlate with the loss and restoration of innate immune functions of blood neutrophils (chemotaxis and reactive oxygen species production), respectively. Quantitative measurements of C5aR on blood neutrophils are highly predictive of survival or death during sepsis. These data suggest that neutrophil C5aR content represents an essential component of an efficient defense system in sepsis and may serve as a prognostic marker for the outcome.

Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression.

IL-6 is known to be an important pro- and anti-inflammatory cytokine, which is up-regulated during sepsis. Our previous work has suggested a role for IL-6 in the up-regulation of C5aR in sepsis. We reported earlier that interception of C5a or C5aR results in improved outcomes in experimental sepsis. Using the cecal ligation/puncture (CLP) model in mice, we now demonstrate that treatment with anti-IL-6 Ab (anti-IL-6) results in significantly improved survival, dependent on the amount of Ab infused. CLP animals showed significantly increased binding of 125I-labeled anti-C5aR to organs when compared to either control mice at 0 h or CLP animals infused with normal rabbit 125I-labeled IgG. Binding of 125I-labeled anti-C5aR to lung, liver, kidney, and heart was significantly decreased in anti-IL-6-treated animals 6 h after CLP. RT-PCR experiments with mRNA isolated from various organs obtained 3, 6, and 12 h after CLP demonstrated increased C5aR mRNA expression during the onset of sepsis, which was greatly suppressed in CLP mice treated with anti-IL-6. These data suggest that IL-6 plays an important role in the increased expression of C5aR in lung, liver, kidney, and heart during the development of sepsis in mice and that interception of IL-6 leads to reduced expression of C5aR and improved survival.