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Context.—Salivary gland-type tumors (SGTs) of the lung represent a distinct group of lung neoplasms. Pulmonary SGTs often pose diagnostic challenges, especially in small biopsy and cytology samples because of limited sample volume and overlapping morphology among pulmonary SGTs, metastatic SGTs of head and neck origin, and other lung tumors.Objective.—To identify the clinical characteristics, histomorphology, immunophenotypic features, and molecular alterations that are crucial for the diagnosis and differential diagnosis of pulmonary SGTs, especially in small biopsy and cytology specimens.Data Sources.—Literature review and authors' personal practice experience.Conclusions.—An accurate diagnosis of pulmonary SGTs can be achieved by careful evaluation of clinical findings and histomorphology in conjunction with immunohistochemical studies and molecular analysis.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal neoplasm typically arising on the face of older individuals, most commonly around the eyelids. Histopathologic features include a circumscribed proliferation of low-grade epithelioid cells with areas of cystic and cribriform growth, foci of intracytoplasmic and extracellular mucin, and coexpression of endocrine, neuroendocrine, and cytokeratin markers by immunohistochemistry. Given histopathologic and immunohistochemical similarities, EMPSGC is often likened to solid papillary carcinoma of the breast and endocrine ductal carcinoma in situ, and is thought by many to represent a forme fruste of mucinous carcinoma of the skin. To date, the vast majority of reported cases of EMPSGC have been described as having indolent behavior, with no cases of distant metastasis yet reported. Here we report a unique case of EMPSGC that recurred over several years following standard surgical excision and Mohs micrographic surgery, with subsequent metastasis to the parotid gland and axial skeleton.

In this study, we investigate the effect of including ridged disk vanes on the operation of a magnetically insulated transmission line oscillator (MILO) in an experiment using a comparison of a ridged MILO (RMILO) with a conventional MILO (CMILO). The only technical difference between the two models is the presence of ridges in the RMILO. The experimental results show that when the voltage is 486 kV and the current is 51 kA, the RMILO’s peak microwave power is approximately 2.9 GW with a pulse duration of more than 35 ns and a microwave frequency of approximately 1.48 GHz. In contrast, the CMILO has the highest power microwave with a peak power of 2.1 GW corresponding to a pulse duration of more than 40 ns and a microwave frequency of approximately 1.53 GHz. The RMILO’s power efficiency increases to 11.7%, a 25% increase compared to that of the CMILO under the same conditions. The experimental measurements exactly coincide with the simulation results. Thus, including ridged disk vanes produces a superior performance.

In this study, we investigate the effect of the inclusion of ridged disk vanes on the operation of a magnetically insulated transmission line oscillator (MILO), using a combination of “cold” (without electron beam) and “hot” (with electron beam) simulations. Cold simulation shows that the inclusion of ridged-disks in a ridged MILO (RMILO) enhances its slow wave structure’s (SWS’s) coupling impedance, thus improving its power efficiency. Moreover, since the ridges’ effect on frequency is weak, the MILO’s inherent tunability is maintained. In hot simulation, the RMILO obtains a 3-dB tunable frequency range of 0.96–2.18 GHz with an applied voltage of 603 kV, in contrast to the 1.04–2.01-GHz range obtained with a conventional MILO (CMILO), owing to the former’s improved power efficiency. With this voltage, the device generates the high power microwave (HPM) with a maximum output power of 7.1 GW at a frequency of 1.40 GHz, corresponding to a power efficiency of 22.6%. The maximum power efficiency of 24.5%, corresponding to a 13.5-GW output, was obtained by increasing the applied voltage to 807 kV, an increase of 20.2% compared to the power efficiency obtained with a CMILO in the same condition.

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. Methods In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. Findings The median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. Interpretation The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. Funding None.

Sand control measures in horizontal wells are mainly based on screens. Horizontal wells have a certain length of horizontal displacement and the kick-off section with large curvature. Therefore, it is necessary to evaluate the safety of the screen downhole run before it runs into the hole, in order to minimize the running risk. In this paper, the pipe string is divided into sections, and the equivalent force for each elementary section is analyzed. Then, the axial force and friction resistance of the pipe string are calculated. According to the buckling criterion of the string and the mechanical strength theory, this paper evaluates whether the screen can safely and smoothly run down to the bottom of the well. This analytical method of solving the physical model is feasible and easy to understand and can be implemented using computer programming applications.

Sarcomas infrequently arise in the larynx where the vast majority of tumors are of epithelial origin. Given their rarity, studies of these lesions are limited in number. In this series, we describe our institutional experience with ten primary sarcomas of the larynx encountered over an 18 year period, comprising 1.9% of all laryngeal malignancies observed in this timeframe. The cases include four chondrosarcomas and one example each of osteosarcoma, embryonal rhabdomyosarcoma, undifferentiated spindle cell sarcoma, well-differentiated liposarcoma, Kaposi sarcoma, and synovial sarcoma. Patients included nine males and one female, with a mean age of 59 years (range 34–75). The mean clinical follow-up time was 3.4 years (range 0–12 years). Clinically, all patients presented with vocal and/or respiratory symptoms, and all received surgical treatment with the exception of the case of Kaposi sarcoma. Of the nine patients who underwent surgical excision, two, both chondrosarcomas, experienced local recurrence. No instances of distant metastasis or death of disease had occurred at the time of preparation of this manuscript. In conclusion, primary sarcomas of the larynx are rare but tend to present with early symptoms. This likely allows for earlier detection and intervention as compared to their counterparts in other deep soft tissue locations. Pathologically, it is important, although difficult in some cases, to distinguish these neoplasms from sarcomatoid carcinoma and reactive processes. Careful morphologic and immunohistochemical evaluation, as well as correlation with the clinical and radiologic findings, is important for accurate tumor classification.

Background β-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. Objective The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia. Methods A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3–deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm. Results Western blotting showed β-catΔE3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3−/− and CTNNB1 E3+/− mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3−/− cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that β-catΔE3 interacted with TCF4 in CTNNB1 E3−/− cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3−/− ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3−/−, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. Conclusion Enhancement of β-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.

The BIG Data Center at Beijing Institute of Genomics (BIG) of the Chinese Academy of Sciences provides a suite of database resources in support of worldwide research activities in both academia and industry. With the vast amounts of multi-omics data generated at unprecedented scales and rates, the BIG Data Center is continually expanding, updating and enriching its core database resources through big data integration and value-added curation. Resources with significant updates in the past year include BioProject (a biological project library), BioSample (a biological sample library), Genome Sequence Archive (GSA, a data repository for archiving raw sequence reads), Genome Warehouse (GWH, a centralized resource housing genome-scale data), Genome Variation Map (GVM, a public repository of genome variations), Science Wikis (a catalog of biological knowledge wikis for community annotations) and IC4R (Information Commons for Rice). Newly released resources include EWAS Atlas (a knowledgebase of epigenome-wide association studies), iDog (an integrated omics data resource for dog) and RNA editing resources (for editome-disease associations and plant RNA editosome, respectively). To promote biodiversity and health big data sharing around the world, the Open Biodiversity and Health Big Data (BHBD) initiative is introduced. All of these resources are publicly accessible at http://bigd.big.ac.cn.

BackgroundSARS-CoV-2 is the cause of an ongoing pandemic with a projected 100,000 to 240,000 U.S. deaths. To date, documentation of histopathologic features in fatal cases of COVID-19 has been limited due to small sample size and incomplete organ sampling.MethodsPost-mortem examinations were performed on 12 fatal COVID-19 cases in Washington State during February-March 2020. Clinical and laboratory data were reviewed. Tissue examination of all major organs was performed by light microscopy and electron microscopy. The presence of viral RNA in sampled tissues was tested by RT-PCR.ResultsAll 12 patients were older with significant preexisting comorbidities. The major pulmonary finding was diffuse alveolar damage in the acute and/or organizing phases with virus identified in type I and II pneumocytes by electron microscopy. The kidney demonstrated viral particles in the tubular epithelium, endothelium, and podocytes without significant inflammation. Viral particles were also observed in the trachea and large intestines. SARS-CoV-2 RNA was detected in the cardiac tissue of a patient with lymphocytic myocarditis. RT-PCR also detected viral RNA in the subcarinal lymph nodes, liver, spleen, and large intestines.ConclusionSARS-CoV-2 represents the third novel coronavirus to cause widespread human disease since 2002. Similar to SARS and MERS, the primary pathology was diffuse alveolar damage with virus located in the pneumocytes. However, other major organs including the heart and kidneys may be susceptible to viral replication and damage leading to increased mortality in those with disseminated disease. Understanding the pathology of SARS-CoV-2 will be essential to design effective therapies.

Histopathologic diagnosis of antibody-mediated rejection in posttransplant liver biopsies is challenging. The recently proposed diagnostic criteria by the Banff Working Group on Liver Allograft Pathology require positive C4d immunohistochemical staining to establish the diagnosis. However, the reported C4d staining patterns vary widely in different studies. One potential explanation may be due to different antibody preparations used by different investigators. In this study, posttransplant liver biopsies from 69 patients histopathologically diagnosed with acute cellular rejection, chronic rejection, or recurrent hepatitis C were immunohistochemically stained using 2 polyclonal anti-C4d antibodies. On the basis of the distribution of C4d immunoreactivity, 5 different staining patterns were observed: portal vein and capillary, hepatic artery, portal stroma, central vein, and sinusoids. The frequency, extent, and intensity of positive C4d staining with the 2 antibody preparations differed significantly for portal veins/capillaries and central veins, but not for hepatic arteries and portal stroma. Positive sinusoidal staining was seen in only 1 case. There were no significant differences in the frequency, extent, and intensity of positive C4d staining among the acute cellular rejection, chronic rejection, and recurrent hepatitis C groups with the 2 anti-C4d antibodies. These data show that different anti-C4d antibodies can show different staining patterns, which may lead to different interpretation. Caution is thus needed when selecting C4d antibodies for clinical use to aid in the diagnosis of antibody-mediated rejection.

The existing current standards for electronic transformers are formulated based on the equivalent of traditional electromagnetic transformers and secondary side protection equipments. In this situation, Although these products have can passed the type test, but there are still a large number of electromagnetic compatibility (EMC) problems still appeared in actual operation. In this paper, based on the actual field application, the interference mechanism of the AIS isolating switch and the electromagnetic transient process on the electronic transformers is simulated. The interference model of the transient electromagnetic field to the secondary side of the electronic transformers and the transmission cables are obtained. Then, a field system-level EMC test method of electronic transformers is proposed. This method is based on the actual equipment and wiring conditions in substations, and the anti-strong electromagnetic disturbance ability of the electronic transformers is evaluated under the condition of “conventional” or “unconventional” operations. Finally, Finally, the field application of system-level electromagnetic compatibility test was carried out in the 330kV Xinsheng Substation, and the fault electronic transformer was tested, which proved the effectiveness of the method.

Primary salivary gland-type lung cancer is a heterogeneous group of neoplasms arising from the seromucinous glands of the respiratory tract. Histopathologically, they are identical to salivary gland neoplasms of the head and neck. While mucoepidermoid carcinoma and adenoid cystic carcinoma are overwhelmingly the most common subtypes found in the lung, reports of uncommon subtypes can be found in the literature. We report a case of a 73-year-old woman with primary lung salivary duct carcinoma, mucin-rich variant--an exceedingly rare subtype of an already rare malignant salivary-type neoplasm. One case of primary lung salivary duct carcinoma has been reported in the literature; however, the mucin-rich variant has never been described in the lung. Furthermore, the tumor in our case bears a rare BRAF G464V mutation. To our knowledge, this is the first reported case of a BRAF G464V mutation detected in a salivary duct carcinoma or any other salivary-type neoplasm.

Malignant mesotheliomas are rather uncommon neoplasms associated primarily with asbestos exposure; however, they may also arise as second primary malignancies after radiation therapy, with a latency period of 15–25 years. Numerous studies have reported an association between pleural malignant mesothelioma and chest radiation performed for other malignancies; on the other hand, post-irradiation mesotheliomas of the pericardium have been reported in only a few published cases to date, and no homozygous deletion of 9p21 has been described in such cases. We report the case of a 48-year-old man with a history of Hodgkin's lymphoma and no prior asbestos exposure who developed pericardial malignant epithelioid mesothelioma. We further discuss the cytologic, histologic, immunophenotypic, and fluorescence in situ hybridization findings in this case. To our knowledge, this is the first well-documented case of post-radiation pericardial malignant mesothelioma showing homozygous deletion of 9p21. Homozygous deletion of 9p21, the locus harboring the p16 gene, is present in post-irradiation pericardial malignant mesothelioma.

Background: Pulmonary sclerosing pneumocytoma (PSP) typically presents solitary and peripheral mass, while only rarely cases display unusual multiple lesions. We reported a extremely rare case of PSP with diffusely-scattered nodules in the right lung. Case presentation: Diffusely round-shaped nodular shadows in the right lung were found by CT scan in a 31-year-old Chinese woman. The patient undergone the right pneumnectomy. Grossly, numerous small nodules, up to 2.5 cm in greatest dimension were identified in the upper, middle and lower lobes of the right lung. Histologically, the tumor presented the typical features of PSP, with a variable proportion of solid, sclerotic and papillary patterns. Immunohistochemical staining further revealed that cuboidal surface epithelial cells were positive for TTF-1, EMA, AE1/3 and vimentin (partially), and round or polygonal cells expressed TTF-1, vimentin, EMA (weakly), synaptophysin (partially), progesterone receptor (partially), and estrogen receptor (scatteredly). The patient has been followed up for 83 months after surgery by annual chest CT and no new lesions are detected in her left lung and other organs. The whole-exome sequencing identified 15 somatic mutations genes (MEGF6, DNAH5, AKT1, GPRIN2, PIK3AP1, FBXO40, HERC1, VPS16, MORN1, ZNF474, CTNNB1, ZNF251, TSC1, ATM, KDR). Pathway analysis showed possible pathways like the components of CTNNB1, AKT1, and TSC1 mutations in the PI3K/AKT signalings and AKT1, KDR and ATM in VEGF signaling pathway and AKT1 activation seemed closely related with these pathways. Conclusion: According to our and previous data, PSP with diffuse or multiple lesions is very rare, and the patients are most commonly seen in women in Asian countries. The misdiagnosis rate by clinical and intraoperative frozen-section assessment is high because of the multiple nodules in the lung and its confusing histological features. Long time follow up indicates surgical resection should not be considered as the preferred strategy for treating multiple PSP in the intralobar sites. AKT1 activation may contribute to the development of PSP while the pathogenesis of diffuse or multiple PSP still needs to be further analyzed.

Context.—A vast majority of neoplasms arising from lung or pleura are initially diagnosed based on the histologic evaluation of small transbronchial, endobronchial, or needle core biopsies. Although most diagnoses can be determined by morphology alone, immunohistochemistry can be a valuable diagnostic tool in the workup of problematic cases.Objective.—To provide a practical approach in the interpretation and immunohistochemical selection of lung/pleura–based neoplasms obtained from small biopsy samples.Data Sources.—A literature review of previously published articles and the personal experience of the authors were used in this review article.Conclusion.—Immunohistochemistry is a useful diagnostic tool in the workup of small biopsies from the lung and pleura sampled by small biopsy techniques.

Orbital atherectomy (OA) is indicated for facilitating stent delivery in patients by reducing coronary plaque, but complete understanding of the therapeutic mechanism has not been established. We performed a mechanistic study using a cadaveric heart perfusion model to investigate the impact of OA on

Mutation analysis of epidermal growth factor receptor (EGFR) is essential in determining the therapeutic strategy for lung adenocarcinoma. Immunohistochemical (IHC) staining with EGFR mutation-specific antibodies of del E746-A750 in exon 19 and L858R in exon 21 has been evaluated in resection specimens in a few studies but rarely in biopsy samples. A total of 169 cases (78 biopsies and 91 resected specimens) of lung adenocarcinoma with EGFR mutation status predefined by direct DNA sequencing were histologically examined, and IHC was performed using EGFR mutation-specific antibodies of del E746-A750 and L858R. The cases with positive results by IHC but negative results by direct DNA sequencing were examined by amplified refractory mutation system. Our results showed that the frequency of EGFR mutations for both E746-A750 deletion and L858R mutation was 38.5% (65/169) by DNA sequencing or amplified refractory mutation system and 34.3% (58/169) by IHC in lung adenocarcinomas. Based on molecular test results, the overall sensitivity, specificity, positive predictive value, and negative predictive value of IHC using these 2 antibodies in all (biopsy/resection) cases were 87.7% (80%/94.3%), 99.0% (97.9%/100%), 98.3% (96%/100%), and 92.8% (88.7%/96.6%), respectively. Lung adenocarcinomas with a predominant acinar, papillary, lepidic, or solid growth pattern more often harbor EGFR mutation of del E746-A750 or L858R. In conclusion, the immunostaining with EGFR del E746-A750 and L858R mutation antibodies is a reliable screening method with high specificity and sensitivity for identifying the EGFR mutation in both resected and biopsied lung adenocarcinomas.

Approximately 5% to 15% of central nervous system metastases by solid tumors spread to the leptomeninges. Transmembrane MUC16 is thought to facilitate anchoring of metastases to other tissues particularly those expressing mesothelin such as pleura and peritoneum. Recently, we have demonstrated that mesothelin is also expressed in the leptomeninges. Mesothelin has a high affinity for MUC16 and mesothelin expressed by some adenocarcinomas. In this study, we evaluated MUC16 and mesothelin immunoreactivity by immunohistochemistry in 11 adenocarcinomas to the leptomeninges, 24 to mesothelin-negative brain, 8 metastases to mesothelin-expressing peritoneum/pleura, 22 to mesothelin-negative peripheral tissues, and 24 with no metastases. MUC16 was detected in 36% of leptomeningeal metastases and 10% of metastases to the brain. Adenocarcinoma metastases to mesothelin-expressing peritoneum or pleura exhibited extensive MUC16 in 75% of cases. In adenocarcinomas with local metastases to lymph nodes or no metastases, 53% or 38% had MUC16 immunoreactivity, respectively. Mesothelin-immunoreactivity was detected in 9% of metastases to the leptomeninges, 17% to the brain, none of the metastases to pleura/peritoneum, 50% of adenocarcinomas with local metastases to lymph nodes, etc, and 33% of adenocarcinomas without metastases. Mesothelin expression was significantly more common in nonmetastatic adenocarcinomas than in metastases to the pleura/peritoneum or leptomeninges. Our findings suggest that adenocarcinomas with MUC16 expression may have an increased risk for metastases to pleura/peritoneum but not the leptomeninges or brain.

Background: Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3 ), a member of the insulin-like growth factor mRNA-binding protein family, is expressed in several human malignancies, including melanomas. However, the expression of IMP-3 has not been explored in melanoma in situ, various histologic subtypes of invasive melanomas and atypical Spitz tumors. Methods: IMP-3 immunostain was performed in 157 melanocytic lesions. Results: Nearly all benign (8/8), dysplastic (8/8) and Spitz nevi (8/9) were negative for IMP-3. Focal IMP-3 positivity was observed in 5/12 melanoma in situ and 4/15 superficial melanomas (Breslow depth ≤1 mm). Half (10/20) of deep melanomas (Breslow depth >1 mm) and 25/52 metastatic melanomas demonstrated strong IMP-3 staining. IMP-3 expression differs significantly between non-desmoplastic melanomas (superficial and deep) and benign or dysplastic or Spitz nevi (p = 0.0427, respectively). Four of 23 desmoplastic melanomas expressed IMP-3 , which was significantly different from deep melanomas (p = 0.0109). IMP-3 stained 7 of 10 atypical Spitz tumors. The difference between atypical Spitz tumors and Spitz nevi was statistically significant (p = 0.0256). Conclusion: A malignant circumstance, such as non-desmoplastic melanoma or atypical Spitz tumor, can be inferred when IMP-3 is expressed, suggesting potential diagnostic value of IMP-3 in melanocytic lesions. Yu L, Xu H, Wasco MJ, Bourne PA, Ma L. IMP-3 expression in melanocytic lesions.

Malignant solitary fibrous tumor (MSFT) is a rare neoplasm. Three cases of MSFT with unusual features, including 1 pleural and 2 extrapleural, are reported. A 64-year-old woman with a large right thoracic MSFT and episodes of severe hypoglycemia experienced resolution of her hypoglycemia immediately after resection of the MSFT. A 27-year-old woman with primary retroperitoneal MSFT had pulmonary metastases 10 months after resection of the primary tumor. A 54-year-old man with an intracranial solitary fibrous tumor suffered from multiple pulmonary metastases and local recurrence 21 and 28 months after resection of the primary tumor, respectively. All 3 cases of solitary fibrous tumor displayed malignant features. The tumor cells in each case were positive for CD34 and Bcl-2, but negative for cytokeratin, smooth muscle actin, S-100, and c-kit. In addition, the tumor cells in the case with concomitant hypoglycemia were strongly positive for insulin-like growth factor-II. The histopathologic diagnostic criteria for MSFT, the differential diagnosis with other spindle cell tumors, and the mechanism of MSFT-derived hypoglycemia via insulin-like growth factor-II are discussed.

Summary Aims Uncommon cases of lung metastasis from different types of uterine neoplasms with a long tumour-free interval after hysterectomy are reported. Methods and results Four cases were retrieved from our surgical pathology archives. Case 1 was a 68-year-old woman who had three pulmonary nodules 23 years after hysterectomy for low-grade endometrial stromal sarcoma (LGESS). The nodules obtained with video-assisted thoracic surgeries were consistent with metastatic LGESS. Case 2 was a 36-year-old woman who had numerous bilateral pulmonary nodules 6 years after hysterectomy for leiomyoma. A transthoracic biopsy revealed benign metastasising leiomyoma. Case 3 was a 77-year-old woman who had a large lung mass with satellite nodules 17 years after hysterectomy with bilateral salpingo-oophorectomy and subsequent radiotherapy for endometrial endometrioid adenocarcinoma (EEA). The biopsied and resected lung tumour was consistent with metastatic EEA. Case 4 was a 51-year-old woman who underwent total hysterectomy and subsequent radiotherapy for endocervical adenocarcinoma 12 years ago and lung lobectomy for metastatic disease 8 years ago. She then developed two pulmonary lesions 14 months ago, and these resected after radiotherapy were metastatic endocervical adenocarcinoma. Conclusions A review of the literature revealed that late pulmonary metastasis from uterine neoplasms is rare but not negligible. Immunohistochemical studies and molecular tests, together with detailed clinical information and imaging findings, are important for rendering a diagnosis.

Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3), also known as K homology domain-containing protein overexpressed in cancer (KOC) and L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and is expressed during embryogenesis and in some malignancies. IMP-3 expression in melanocytic neoplasms has not been investigated. Fifty-six melanocytic neoplasms from 48 subjects were immunohistochemically studied using a monoclonal antibody against L523S/IMP-3. IMP-3 expression in melanoma was significantly higher than in Spitz nevi (P

BACKGROUND. Immunohistochemistry is helpful in distinguishing metastatic carcinoma from atypical mesothelial cells; however, it is not useful in differentiating atypical mesothelial cells from malignant mesothelial cells. K homolog domain containing protein overexpressed in cancer (KOC), a member of the insulin-like growth factor mRNA-binding protein (IMP) family, also known as L523S and IMP3, is expressed during embryogenesis and in various malignancies. Using a mouse monoclonal antibody (L523S) against KOC, KOC expression was investigated in malignant tumors and reactive mesothelial cells in serous effusions. METHODS. Seventy-six cases with paraffin-embedded pleural, pericardial, and peritoneal serous effusion cell blocks including 60 malignant serous effusions (11 malignant pleural mesotheliomas and 49 metastatic carcinomas) and benign pleural effusions (14 cases with reactive mesothelial cells and 2 cases with atypical cells with uncertain significance) were selected for immunohistochemical analysis with L523S, calretinin, and CK5/6. RESULTS. Immunohistochemical studies showed that positive staining for KOC of variable degrees of intensity was observed in 47 of 60 cases in malignant serous effusions including 10 of 11 mesotheliomas and 36 of 49 metastatic carcinomas. The associated reactive mesothelial cells were negative for KOC but positive for calretinin and CK5/6. All 11 malignant mesotheliomas exhibited positivity for calretinin, and 9 of 11 cases had CK5/6 staining. In addition, 16 cases that were originally diagnosed either as pleural effusions with reactive mesothelial cells (14) or atypical cells with uncertain significance (2) were also tested for KOC expression. Interestingly, 3 of 16 cases exhibited various degrees of positivity for KOC, 2 of which were diagnosed as lung adenocarcinoma with a recurrence after tumor resection and 1 as malignant pleural mesothelioma. CONCLUSIONS. Anti-L523S antibody is a useful marker for the detection of malignant cells in serous effusions and it can have significant utility in differentiating reactive mesothelial cells from malignant mesothelioma and metastatic carcinoma in combination with calretinin and CK5/6 staining. Cancer (Cancer Cytopathol) 2008. © 2007 American Cancer Society.

It has been shown that tyrosine kinase oncoprotein c-kit and antiapoptotic molecule bcl-2 are overexpressed in several types of malignancy, including small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung. Whether these 2 molecules are coexpressed in lung neuroendocrine tumors has not been investigated. Here, we analyzed immunohistochemical results to determine expression and coexpression patterns of c-kit and bcl-2 in the spectrum of lung neuroendocrine tumors. Using a polyclonal antibody against c-kit and a monoclonal antibody against bcl-2, our data demonstrated that all 7 cases (100%) of SCLC included in this study were positive for both c-kit and bcl-2. Among 14 LCNECs, 7 (50%) stained positive for c-kit and 9 (64%) for bcl-2. All cases of high grade neuroendocrine carcinomas (SCLCs and LCNECs) that showed positive staining for c-kit coexpressed bcl-2. In contrast, all typical and atypical carcinoids (TC and AC) were negative for c-kit, and only 1 of 16 (6.3%) TCs and 1 of 6 (16.7%) ACs stained positive for bcl-2. These results indicate a progressive increase in the frequency of c-kit and bcl-2 expression and coexpression, from carcinoid tumors (TC and AC) to LCNEC and to SCLC. High grade neuroendocrine carcinomas are more likely to coexpress c-kit and bcl-2 when compared with carcinoid tumors. The high frequency of coexpression of these 2 molecules in high grade neuroendocrine carcinomas of the lung suggests that they may be involved in the carcinogenic pathway, given their important roles in carcinogenesis. Therapeutic targeting on both c-kit and bcl-2 molecules might be beneficial in the management of patients with high grade neuroendocrine carcinomas of the lung in the future.

Malakoplakia is a rare inflammatory disorder that results from an infectious process and that may be associated with immunosuppression. It most often occurs in the genitourinary tract; however, isolated cases have been reported in many other organs, including colon, stomach, lung, liver, bone, uterus, and skin. In the bladder, which is the most common site of involvement, it may be mistaken for malignancy on cystoscopic examination or computerized topography scan. Gram-negative bacteria such as Escherichia coli and Klebsiella pneumonia are often isolated from malakoplakia lesions, although other less common bacteria such as Rhodococcus equi may also be found. This is a case report of prostatic malakoplakia diagnosed on needle core biopsy from a patient suspected to harbor a malignancy.

Summary Objective Discern inter- and intra-observer variability in the classification of extracapsular extension (ECE) in p16+ oropharyngeal (OP) SCC comparing pathologists’ own criteria versus those of a well-defined classification system. Methods Five pathologists reviewed 50 digitally scanned nodal metastasis slides in three Rounds. Round One was by their own criteria as ECE present or absent, and Rounds Two and Three were with a defined ECE system: Grade 0 (no ECE), 0c (no ECE – thick capsule; no infiltration), 1 (ECE – cells beyond capsule), and 2 (soft tissue metastasis – cells in soft tissue without residual node). Round Three assessed intra-observer variability after an 8 month washout period. Results In Round One, all five agreed on only 48% of cases (n = 24). Fleiss’s Kappa value was 0.508 (95% CI: 0.357–0.644). For Rounds Two and Three, Grades 0 and 0c and Grades 1 and 2 were separately grouped as ECE absent or present. In Round Two, all five agreed on 68% of cases (n = 34). Fleiss’ Kappa was 0.635 (95% CI: 0.472–0.783), indicating statistically significantly better agreement. In Round Three, all five agreed on 64% of cases (n = 32) giving a Fleiss’s Kappa of 0.639. Pathologists agreed with their prior reads in approximately 90% of cases (average n = 45.4, range n = 42–49), an average intra-observer Cohen’s Kappa of 0.8 (range: 0.68–0.95). Inter- and intra-observer variability rates for classification of soft tissue metastasis (ECE2) were substantially worse. Conclusion There is substantial inter-, and modest intra-, observer variability among head and neck pathologists for ECE in p16+ OPSCC, which is modestly improved by a defined system.

Patent foramen ovale and atrial septal aneurysm are associated with an increased risk of cryptogenic stroke and recurrent thromboembolic events. Percutaneous closure is a therapeutic option to medical therapy and surgical closure. We present the first case of endocarditis associated with a CardioSEAL device closing a patent foramen ovale.

BACKGROUND Metastasis-associated in colon cancer-1 (MACC1), a newly identified regulator of HGF-MET signaling, may participate into the key steps of sporadic colorectal adenocarcinoma development. Given there are many pathogenetic distinctions between colitis-associated colorectal cancer (CAC) and sporadic colorectal adenocarcinomas, the potential roles of MACC1 in CAC carcinogenesis remain unknown. For the first time, we evaluated the expressions of MACC1 and MET in IBD-associated colitis, dysplasia, and adenocarcinoma. METHODS Expression was investigated by immunohistochemistry in tissue microarrays consisting of 13 normal colon, 11 active colitis, 9 dysplasia, 51 conventional CAC, 5 mucinous adenocarcinoma, and 1 signet ring cell adenocarcinoma specimens. The expression level of MACC1 or MET was evaluated with H-score system. RESULTS MACC1 expression was significantly higher in IBD-associated dysplasia than that in corresponding inflammatory or normal colonic tissue, and its level was further elevated from dysplasia to conventional CAC. Higher MACC1 expression was seen in a patient with CAC who had multifocal dysplasia or synchronous carcinoma. MACC1 overexpression (H-score >100) was seen in 67% of conventional CAC but in 0% of dysplasia and 0% of inflammation or normal colon. There was no difference of MACC1 expression found among well, moderately and poorly differentiated CAC. MET expressions in inflammation, dysplasia, and conventional CAC were statistically similar. No parallel expression of MACC1 and MET was detected in this study. MACC1 and MET expression was not increased in mucinous or signet ring cell carcinoma, 2 distinct variants of CAC. CONCLUSIONS Stepwise increase of MACC1 expression from IBD-associated colitis to dysplasia to adenocarcinoma suggests that MACC1 is strongly associated with conventional CAC tumorigenesis in a manner independent of MET. MACC1 may serve as a potential marker for early diagnosis of conventional CAC.

D2-40 is a new monoclonal antibody recognizing podoplanin and it is selective for lymphatic endothelium. Several studies have confirmed the reliability of D2-40 in the diagnosis of pleural malignant mesothelioma, but the evaluation of this antibody in other pleural neoplasms is limited. The aim of this study was to determine the diagnostic value of D2-40 in segregation of malignant mesothelioma from other pleural or lung neoplasms. Sixty-seven cases, including 36 pleural malignant mesotheliomas, 15 solitary fibrous tumors, 13 pleomorphic carcinomas, and 3 synovial sarcomas, were immunohistochemically studied using a D2-40 monoclonal antibody. Twenty-five (21 epithelioid and 4 biphasic) of 36 (69%) malignant mesotheliomas and 2 of 15 (13%) solitary fibrous tumors were positive for D2-40. The difference of D2-40 positivity between these 2 types of tumor was significant (P

Introduction: Almost all small-cell lung cancers (SCLC) and carcinoid tumors express neuroendocrine differentiation (NED), and 10% to 20% of non–small-cell lung cancers (NSCLC) are associated with NED. Although distinct clinical features and histology of SCLC and carcinoid tumors are well recognized, the clinical significance and the molecular basis of NED in NSCLC remain unclear. Methods: To explore the potential molecular pathway involved in NED of NSCLC and its clinical relevance, we conducted investigations using an NSCLC cell line (NCI-H157) as a NED induction model, and explored the potential intracellular signal transduction pathways involved in NED of NSCLC. We confirmed our findings using activators versus inhibitors to these signal transduction pathways in vitro. We also performed immunohistochemical stains of phospho-Erk1/2 of lung cancer specimens known to have NED and explored its clinical relevance. Results: We discovered that NED of NSCLC was associated with the activation of Erk1/2-mitogen-activated protein kinases (MAPK) signal transduction pathway, and the inhibition of the Akt signal transduction pathway. Using specific activator (Pb2+) and inhibitors (siRNA-Erk1/2 and U0126) to the Erk1/2-MAP-kinase pathway, as well as the inhibitor (LY294002) to the Akt pathway, we found that Erk1/2-MAP-kinase activation was essential for NED of NCI-H157 cells. Staining of Erk1/2-MAP-kinase pathway revealed a high rate of positivity in NSCLC tumors with NED when compared with other neuroendocrine lung tumors. Conclusions: To our knowledge, our findings are the first to describe the potential involvement of Erk/MAPK signal transduction pathway of NSCLC in the association with NED. Further investigation of the Erk/MAPK signal transduction pathway of NSCLC may yield discoveries in identifying specific molecular targets for the treatment of NSCLC with NED.

Parathyroid adenoma with prominent lymphocytic infiltrates is very rare, with only 8 previously reported cases in the English scientific literature. Cases with prominent lymphocytic infiltrates of ectopic (mediastinal) parathyroid adenomas have not been reported. The prominent lymphocytic infiltration may make the diagnosis difficult on frozen sections, even on permanent histologic sections. We herein describe a case of ectopic (mediastinal) parathyroid adenoma with prominent lymphocytic infiltration in a 29-year-old man with hyperparathyroidism for 4 years. Immunohistochemical studies were important in making such a diagnosis.

Primary ovarian carcinoids and metastatic tumors share similar morphologic features. Metastatic carcinoids must be excluded from primary ones for prognostic and therapeutic reasons. Gastrointestinal neuroendocrine (carcinoid) tumors are much more common with the majority arising from small intestine and appendix. The aim of this study is to evaluate the role of immunohistochemistry for CDX2 in differentiating primary ovarian from metastatic carcinoids of primary gastrointestinal origin. Thirty primary pure ovarian carcinoids, 16 primary ovarian carcinoids arising in association with benign teratomas, 10 ovarian carcinoids metastatic from primary gastrointestinal tract and 70 gastrointestinal neuroendocrine tumors were studied for the expression of CDX2 by immunohistochemistry. CDX2 expression revealed that 40 (57.1%) of 70 cases of gastrointestinal carcinoids and 9 (90%) of 10 ovarian metastatic carcinoids showed positive nuclear staining (diffuse or focal). On the other hand, 3 (18.8%) of 16 primary carcinoids with teratomatous elements showed weak positivity. Among the 70 gastrointestinal carcinoids, CDX2 was positive in 38 (90.5%) of 42 cases in the duodenum, small intestine, appendix, and only in 2 (11.8%) of 17 cases of colorectal carcinoids and none of the 11 cases in the stomach. It is concluded that CDX2 may be a useful marker to distinguish primary ovarian carcinoid from metastasis from small intestinal and appendiceal neuroendocrine tumors.

Background— Diabetes mellitus is a major risk factor for cardiovascular mortality by increasing endothelial cell (EC) dysfunction and subsequently accelerating atherosclerosis. Extracellular-signal regulated kinase 5 (ERK5) is activated by steady laminar flow and regulates EC function by increasing endothelial nitric oxide synthase expression and inhibiting EC inflammation. However, the role and regulatory mechanisms of ERK5 in EC dysfunction and atherosclerosis are poorly understood. Here, we report the critical role of the p90 ribosomal S6 kinase (p90RSK)/ERK5 complex in EC dysfunction in diabetes mellitus and atherosclerosis. Methods and Results— Inducible EC-specific ERK5 knockout (ERK5-EKO) mice showed increased leukocyte rolling and impaired vessel reactivity. To examine the role of endothelial ERK5 in atherosclerosis, we used inducible ERK5-EKO-LDLR −/− mice and observed increased plaque formation. When activated, p90RSK associated with ERK5, and this association inhibited ERK5 transcriptional activity and upregulated vascular cell adhesion molecule 1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced endothelial nitric oxide synthase expression. p90RSK activity was increased in diabetic mouse vessels, and fluoromethyl ketone-methoxyethylamine, a specific p90RSK inhibitor, ameliorated EC-leukocyte recruitment and diminished vascular reactivity in diabetic mice. Interestingly, in ERK5-EKO mice, increased leukocyte rolling and impaired vessel reactivity were resistant to the beneficial effects of fluoromethyl ketone-methoxyethylamine, suggesting a critical role for endothelial ERK5 in mediating the salutary effects of fluoromethyl ketone-methoxyethylamine on endothelial dysfunction. Fluoromethyl ketone-methoxyethylamine also inhibited atherosclerosis formation in ApoE −/− mice. Conclusions— Our study highlights the importance of the p90RSK/ERK5 module as a critical mediator of EC dysfunction in diabetes mellitus and atherosclerosis formation, thus revealing a potential new target for therapeutic intervention.

Colonic inertia is a frustrating motility disorder to patients, clinicians, and pathologists. The pathogenesis is largely unknown. The aims of this study were to: (1) characterize the expression of smoothelin, a novel smooth muscle-specific contractile protein expressed only by terminally differentiated smooth muscle cells, in the normal gastrointestinal (GI) tract; and (2) determine whether smoothelin is aberrantly expressed in patients with colonic inertia. A total of 57 resections of the normal GI tract (distal esophagus to left colon) were obtained from patients without GI motor dysfunction. Sixty-one colon resections were obtained from patients with a clinical diagnosis of colonic inertia. Smoothelin immunostaining was conducted on full-thickness tissue sections. In the nondysmotile controls, strong and diffuse cytoplasmic staining for smoothelin was observed in both the inner circular and outer longitudinal layers of the muscularis propria (MP) throughout the entire GI tract. The muscularis mucosae (MM) and muscular vessel walls were either completely negative or only patchily and weakly stained. The 1 exception to this pattern was observed in the distal esophagus, in which the MM was also diffusely and strongly stained. In cases with colonic inertia, a moderate to marked reduction of smoothelin immunoreactivity was observed in 15 of 61 (24.6%) colon resections, selectively seen in the outer layer of the MP. The data demonstrate that smoothelin is differentially expressed in the MP and MM of the normal GI tract and suggest that defective smoothelin expression may play a role in the pathogenesis of colonic inertia in a subset of patients. Copyright © 2012 by Lippincott Williams & Wilkins.

These multimedia modules have been developed to teach senior medical students on their surgical pathology elective the basic microscopic features of common surgical pathology diagnoses. The modules include normal histology and pathology organized into the following organ systems: breast, gastrointestinal, genitourinary, gynecologic, liver, and lung. The first component to this teaching set is a review of normal histology which may serve as a comparison for the histopathology component. A low- and high-power micrograph of each organ is provided. The student is tested with a quiz of micrographs of normal histology where they must identify the organ. Next, students review commonly encountered biopsies in each organ system. Under each diagnosis is listed the definition, etiology, symptoms/indications for biopsy, gross features, microscopic features, and a differential diagnosis. Radiologic features and pertinent additional stains are noted when appropriate. The goal of the surgical pathology rotation at this institution is to allow students to function as junior house officers, actively participating in previewing and sign-out. These teaching modules will provide basic clinical and microscopic descriptions to help the student preview and diagnose biopsy specimens on their own. The clinical implications of certain diagnoses as they pertain to aggressive management in neoplastic disease will also be mentioned. The modules are designed so students can easily navigate between slides, diagnoses, and differentials. Each image is provided with arrows and labels (which may be hidden) to guide the eye of the learner to recognize the patterns of each diagnosis. After completing a module, students will solidify their knowledge with a quiz. We plan to monitor the effectiveness of this assessment by having students take the quiz at the start and end of the rotation to compare the change in their score. These modules will provide an organized foundation on which the student may build his or her knowledge during slide review with senior residents or staff pathologists.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

Histologic evaluation of an endoscopic bile duct biopsy for malignancy is a known challenge. Our prior study has shown that the insulin-like growth factor-II mRNA binding protein-3 (IMP3), S100P, and the von Hippel-Lindau gene product (pVHL) are a useful immunopanel for the distinction between adenocarcinoma and benign biliary epithelium. To further evaluate the usefulness of the IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies, 16 histologically challenging bile duct biopsies that exhibited atypical histology or features suspicious for malignancy were immunohistochemically stained for IMP3, S100P, and pVHL. Clinical follow-up data were obtained for each case. The results showed that in the 11 cases that showed adenocarcinoma during follow-up, the following staining patterns in atypical/suspicious cells in the initial biopsies were observed: IMP3-positive/S100P-positive/pVHL-negative or reduced (n=6), IMP3-negative/S100P-positive/pVHL-negative or reduced (n=4), and IMP3-positive/S100P-negative/pVHL-negative (n=1). In the 5 follow-up-proven benign cases, 2 biopsies showed an IMP3-negative/S100P-positive/pVHL-positive pattern in atypical cells and 1 was negative for all 3 proteins. The remaining 2 biopsies exhibited an IMP3-positive/S100P-positive/pVHL-negative or reduced pattern in atypical cells that were histologically considered dysplastic on retrospective review. These observations reaffirm that bile duct adenocarcinoma frequently shows positive IMP3 and/or S100P staining with reciprocal negative or reduced pVHL expression. This staining pattern can also be seen in dysplastic epithelium in the absence of invasive carcinoma. On the contrary, benign biliary epithelium typically lacks IMP3 immunoreactivity and may retain normal pVHL expression. However, caution should be exercised when using this immunopanel in the interpretation of challenging bile duct biopsies, because S100P and pVHL stains may give rise to variable patterns that can be difficult to interpret.

Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and ‘difficult’ histologic patterns. A total number of scores for the typical patterns combined (n = 94) and the difficult cases (n = 21) were 2444 and 546, respectively. The mean kappa score (± s.d.) for the five typical patterns combined and for difficult cases were 0.77 ± 0.07 and 0.38 ± 0.14, respectively. Although 70% of the observers identified 12–65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92–100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as ‘difficult’ examples. The kappa for typical and difficult cases was 0.55 ± 0.06 and 0.08 ± 0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.

Malignant melanoma is the deadliest form of skin cancer arising from the abnormal proliferation of epidermal melanocytes. With the incidence and mortality from this disease rising, accurate histopathologic diagnosis is crucial. Most cases of melanoma can be appropriately diagnosed based on morphologic criteria, but a subset of lesions including Spitz and dysplastic nevi, can be difficult to distinguish from malignant proliferations. In addition, even though current immunohistochemical stains tend to be rather sensitive and specific for most types of malignant melanoma (S-100, MelanA/MART-1, HMB-45 and tyrosinase), they are unable to distinguish malignant from benign melanocytes--a potential pitfall in architecturally and cytologically borderline cases, which can lead to inadequate treatment or surveillance. Also, the distinction between intranodal nevi and metastatic melanoma in sentinel lymph nodes is not morphologically straightforward in certain cases; however, the confirmative status of these lymph nodes is very important for clinical outcome and guiding treatment. Thus, finding a method to precisely distinguish melanoma from its benign mimickers is needed. Despite advances in melanoma investigation and research, no reliable diagnostic biomarkers have yet been identified. Another challenge in melanoma treatment is to determine patients’ prognosis. Currently, depth of invasion, tumor ulceration, and status of sentinel lymph node are three common objective measures of prognosis; with invasion greater than 1 mm, ulceration, and lymph node metastases portending a worse outcome. Other features, such as assignment of radial versus vertical growth phase, tumor infiltrating lymphocytes, and Clark's levels, are also useful for prognosis, but tend to be more subjective. Thus, an immunohistochemical marker predictive of disease progression and poorer prognosis would be useful, to identify melanomas with a more aggressive phenotype.

TTF-1 and napsin A are useful biomarkers for differentiating primary lung adenocarcinoma from metastatic tumors. Studies have shown, however, that TTF-1 and napsin A also can be expressed in extrapulmonary carcinomas, and that a small fraction of primary lung adenocarcinomas do not co-express these two markers. We attempted to determine whether a tissue-specific transcriptional factor, PAX8, can help determine primary sites of lung carcinomas. Immunohistochemical stains for PAX8, TTF-1 and napsin A were performed on 103 cases of metastatic lung carcinomas from a variety of origins and 120 cases of primary lung adenocarcinomas. Our data demonstrated that all 103 metastatic carcinomas were negative for napsin A, while 14 (13.6%; four thyroid, two endometrium, three colon, one prostate, one salivary adenoid cystic, two renal cell carcinomas, and one ovary) showed weak to strong TTF-1 nuclear staining in 5-60% of the tumor cells. All primary lung adenocarcinomas were negative for PAX8, whereas 46 (44.7%) metastatic carcinomas from the kidney (29/33), ovary (6/8), endometrium (5/5), endocervix (1/1), thyroid (4/5) and urinary tract (1/3) were positive for PAX8. Our data demonstrate that of combined use of PAX8, TTF-1 and napsin A is reliable to separate reliably lung primary from metastatic tumors.

Differentiation of primary from metastatic adenocarcinoma in the lung can be challenging, and it demands sensitive and specific biomarkers, especially when the tissue for diagnosis is limited. Thyroid transcription factor-1 (TTF-1) has been considered a reliable marker for adenocarcinoma of lung origin. However, several recent studies have shown that TTF-1 immunostaining is also positive in adenocarcinomas arising in different organs including colon, endometrium, endocervix, and ovary. In addition, approximately 20% of lung primary adenocarcinomas are negative for TTF-1 immunostaining, and napsin A immunostaining has slightly higher sensitivity in detecting lung primary adenocarcinoma. We performed TTF-1 and napsin A immunostaining on 120 cases of primary lung adenocarcinomas and 37 cases of metastatic carcinomas in the lung. The results showed that 95 (79.2%) of 120 lung primary adenocarcinomas showed napsin A+/TTF-1+ double-positive immunostaining pattern. TTF-1⁻/napsin A+, TTF-1+/napsin A⁻, and TTF-1⁻/napsin A⁻ were seen in 8.3%, 3.3%, and 9.2% lung primary adenocarcinomas, respectively. Eight (21.6%) of the 37 metastatic carcinomas were positive for TTF-1 and they include clear-cell renal cell carcinomas completely negative for napsin A although napsin A was detected in 12 (80.0%) of 15 primary papillary and 3 (33.3%) of 9 primary clear-cell renal cell carcinomas. All renal epithelial neoplasms were TTF-1 negative. These findings indicate that double napsin A and TTF-1-positive immunostaining is highly specific for lung primary adenocarcinoma and the combination of these 2 biomarkers is warranted to help segregating primary lung adenocarcinoma from metastatic carcinoma in the lung.

Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin. Measurements and Main Results: TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β–induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/−) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis. Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB–dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.