Interpathologist Diagnostic Agreement for Non-Small Cell Lung Carcinomas Using Current and Recent Classifications.

CONTEXT.­: Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES.­: To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure. DESIGN.­: We used a Web-based survey to present core images of 54 NSCLC cases to 22 practicing pathologists for diagnosis, initially as H&E only, then as H&E plus mucin and 4 IHC stains. Each case was diagnosed according to published 2004, 2011, and 2015 NSCLC classifications. Cohen's kappa was calculated for the 231 pathologist pairs as a measure of IPDA. RESULTS.­: Twenty-two pathologists diagnosed 54 NSCLC cases by using 4 published classifications. IPDA is significantly higher for H&E/mucin/IHC diagnoses than for H&E-only diagnoses. IPDA for H&E/mucin/IHC diagnoses is highest with the 2015 classification. IPDA is estimated higher after collapse of stated diagnoses into subhead or dichotomized classes. IPDA for H&E/mucin/IHC diagnoses with the 2015 World Health Organization classification is similar for community and academic pathologists, and is higher when pathologists have pulmonary pathology expertise, have more than 6 years of practice experience, or diagnose more than 100 new lung carcinoma cases per year. CONCLUSIONS.­: Higher IPDA is associated with use of mucin and IHC stains, with the 2015 NSCLC classification, and with pathologists' pulmonary pathology expertise, practice duration, and frequency of lung carcinoma cases.

Neutral sphingomyelinase 2 deficiency is associated with lung anomalies similar to emphysema.

Neutral sphingomyelinase 2 (nSMase2) upregulation was recently demonstrated to serve as a molecular link between smoke inhalation and emphysematous changes in lungs. Here we report that nSMase2 deficit impairs lung development in mice. We have shown previously that fragilitas ossium (fro) mice carry a mutation in the Smpd3 gene, rendering nSMase2 catalytically inactive. Analysis of lung phenotype revealed that fro mice have abnormally enlarged alveoli and increased compliance of the respiratory system, similar to morphological and functional manifestations of emphysema. Analysis of sphingolipid content in fro lungs revealed a decreased level of C14:0 ceramide but no significant alterations in the levels of sphingosine or sphingosine-1-phosphate. Altogether, our data suggest that nSMase2 activity and ceramide level are critical for lung development and function. Based on our data, ceramide can no longer be viewed as a lipid solely detrimental to lung function.

Biopersistence of refractory ceramic fiber in human lung tissue and a 20-year follow-up of radiographic pleural changes in workers.

OBJECTIVE: The biopersistence of refractory ceramic fiber (RCF) in human lung tissue is unknown and may contribute to an association between cumulative fiber exposure and radiographic changes. METHODS: Lung tissue fiber was analyzed for a case series of 10 RCF workers and a 20-year longitudinal chest radiograph study of 1323 workers was conducted. RESULTS: Within lung tissue, RCF comprised 14% to 100% of fibers 5 µm or more in length and was identified up to 20 years after RCF employment. Among workers with no reported asbestos exposure, cumulative exposure of more than 63 to 110 and more than 110 fiber-months/cm was associated with radiographic pleural changes of 8.5% (odds ratio, 7.2; 95% confidence interval, 1.4 to 36.8) and 11.6% (odds ratio, 10.3; 95% confidence interval, 2.1 to 49.9), respectively. CONCLUSIONS: Refractory ceramic fiber can persist in human lung tissue for up to 20 years and may contribute to the significant association between cumulative fiber exposure and radiographic pleural changes.

Giant, metachronous bilateral dorsalis pedis artery true aneurysms.

This report is the first to describe the clinical, radiographic, operative, and pathologic findings associated with large, bilateral dorsalis pedis artery true aneurysms in a single patient. A 61-year-old African American woman complained of difficulty in wearing shoes. She had a moderately firm, nontender, pulsatile mass on the dorsum of her right foot. Computed tomography and angiography confirmed dorsalis pedis artery aneurysm with sufficient collateralization. She underwent resection without reconstruction. Pathologic analysis revealed a true aneurysm (8 × 5.3 × 4.1 cm(3)) containing intralumenal thrombus. Treatment for small symptomatic and large dorsalis pedis artery aneurysms remains resection with or without reconstruction.

Molecularly confirmed primary malignant rhabdoid tumor of the urinary bladder: implications of accurate diagnosis.

Malignant rhabdoid tumors (MRTs) are well recognized in the kidney and extrarenal sites such as soft tissues, retroperitoneum, and bladder but are classified as atypical teratoid/rhabdoid tumors in the central nervous system. The unifying features of both extracranial MRT and atypical teratoid/rhabdoid tumors are the exon deletions/mutations of the SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) gene in 22q11.23 and resulting loss of SMARCB1/INI1 (integrase interactor 1) protein expression by immunohistochemistry. We herein report a case of extrarenal rhabdoid tumor confined to the bladder in a 3-year-old child, diagnosed by histopathology and confirmed by immunohistochemical and molecular studies. This is only the fourth molecularly proven primary MRT of the bladder to be reported. The patient's peripheral blood was negative for the deletions observed in the tumor, thereby confirming a sporadic origin for the tumor. Given the possible dismal outcome, urgency for definitive diagnosis to institute intensive multimodality therapy, histopathologic differential diagnosis with rhabdomyosarcoma and urothelial carcinoma with rhabdoid features, and lack of consensus management guidelines, oncologists, urologists, and pathologists must be aware of this entity. Evaluation for a germ line SMARCB1 alteration may greatly aid risk stratification and family planning.

A soft-tissue coupling for wound closure.

Wounds often cannot be successfully closed by conventional means of closure such as sutures or staples. Our group developed the FiberSecure™ device to close soft tissue wounds reliably, surpassing native tissue strength. We closed cross-fiber muscle incisions, to evaluate (1) four different configurations of FiberSecure™ for 30 days, then (2) the resulting preferred configuration for 180 days. The four treatment groups each placed 21,504 polyester (PET) 12-µm fibers (cross-sectional area 1% of muscle) traversing the incision, in the form of (A) Four large (No.7 suture) non-textured bundles, (B) Eight small (No.2 suture) non-textured, (C) Four large textured, or (D) Eight small textured. Four incisions were closed in the external oblique muscle of 16 Sinclair minipigs. At 30 days, specimens were removed for biomechanics, histology, and total collagen content. Group (B) was selected for 180-day evaluations in the same wound model in eight animals, four closures each (n = 32), again with biomechanics and histology. In strength testing, every specimen tore through muscle remotely, while the repair region remained intact. Maximum forces were (A) 37.8 ± 3.9 N, (B) 37.1 ± 4.7 N, (C) 39.0 ± 5.3 N, and (D) 32.4 ± 3.4 N at 30 days, and 37.2 ± 11.3 N at 180 days (mean ± SEM). No significant difference was observed among the groups or time points (p > 0.05).

Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas.

Papillary carcinoma is the most common type of thyroid malignancy. It has been recently shown that these tumors commonly have one of three genetic alterations: BRAF point mutations, RET/PTC rearrangements, or RAS point mutations. In this study, we analyze the relationship between these alterations and the microscopic features of papillary carcinomas, their clinical features, and prognostic characteristics. Ninety-seven papillary carcinomas were studied; in all cases, frozen tissue was available for nucleic acid extraction. Of 96 unselected cases, 42% were positive for BRAF, 18% for RET/PTC, and 15% for RAS mutations. Morphologic features were evaluated in detail in 61 cases and 6 characteristic nuclear features and 3 additional microscopic features were assessed quantitatively. At least 4 nuclear features were found in each tumor, with nuclear pseudoinclusions being the least frequent finding in all mutation groups. BRAF mutations were associated with older patient age, typical papillary appearance or the tall cell variant, a higher rate of extrathyroidal extension, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at younger age and had predominantly typical papillary histology, frequent psammoma bodies, and a high rate of lymph node metastases. Tumors with RAS mutations were exclusively the follicular variant of papillary carcinoma and correlated with significantly less prominent nuclear features and low rate of lymph node metastases. These findings demonstrate that BRAF, RET/PTC, and RAS mutations are associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.

Preferences regarding the computerized delivery of lecture content:a survey of medical students.

Available technology allows for the capture and rebroadcast of lectures via computer-based tools. Such tools have the potential to enhance medical education. Medical schools are beginning to offer such services, but little is known about end-user preferences. We surveyed students at one US medical school to gather their preferences for the availability and use of computer-based lecture presentation. These findings add to the limited literature regarding use of such tools for medical education.

Increased staining for phospho-Akt, p65/RELA and cIAP-2 in pre-neoplastic human bronchial biopsies.

BACKGROUND: The development of non-small cell lung carcinoma proceeds through a series of well-defined pathological steps before the appearance of invasive lung carcinoma. The molecular changes that correspond with pathology changes are not well defined and identification of the molecular events may provide clues on the progression of intraepithelial neoplasia in the lung, as well as suggest potential targets for chemoprevention. The acquisition of anti-apoptotic signals is critical for the survival of cancer cells but the pathways involved are incompletely characterized in developing intra-epithelial neoplasia (IEN). METHODS: We used immunohistochemistry to determine the presence, relative levels, and localization of proteins that mediate anti-apoptotic pathways in developing human bronchial neoplasia. RESULTS: Bronchial epithelial protein levels of the phosphorylated (active) form of AKT kinase and the caspase inhibitor cIAP-2 were increased in more advanced grades of bronchial IEN lesions than in normal bronchial epithelium. Additionally, the percentage of biopsies with nuclear localization of p65/RELA in epithelial cells increased with advancing pathology grade, suggesting that NF-kappaB transcriptional activity was induced more frequently in advanced IEN lesions. CONCLUSION: Our results indicate that anti-apoptotic pathways are elevated in bronchial IEN lesions prior to the onset of invasive carcinoma and that targeting these pathways therapeutically may offer promise in prevention of non-small cell lung carcinoma.

BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.

Activating point mutations of the BRAF gene have been recently reported in papillary thyroid carcinomas. In this study, we analyzed 320 thyroid tumors and six anaplastic carcinoma cell lines and detected BRAF mutations in 45 (38%) papillary carcinomas, two (13%) poorly-differentiated carcinomas, three (10%) anaplastic carcinomas, and five (83%) thyroid anaplastic carcinoma cell lines but not in follicular, Hürthle cell, and medullary carcinomas, follicular and Hürthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-->A transversion at nucleotide 1796. In papillary carcinomas, BRAF mutations were associated with older age, classic papillary carcinoma or tall cell variant histology, extrathyroidal extension, and more frequent presentation at stages III and IV. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well-differentiated and dedifferentiated components. These data indicate that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. They are associated with distinct phenotypical and biological properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.

RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.

A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR gamma rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR gamma rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement.

Therapeutic decision making in stages III and IV head and neck squamous cell carcinoma.

BACKGROUND: The best treatment for advanced head and neck cancer remains unclear. Proponents of various therapeutic regimens continue to debate this issue with inconclusive and frequently biased data and with carefully selected patients in controlled trials to support their approach. To assess the outcome of patients in a real-world situation, we reviewed a prospectively maintained database of patients with head and neck cancer. METHODS: We reviewed data from 591 consecutive patients with stage III or IV squamous cell carcinoma treated at a university medical center from January 1, 1992, through December 31, 2000, and analyzed survival using the Kaplan-Meier method. RESULTS: Overall survival was 48%, 40%, and 33% at 2, 3, and 5 years, respectively. We found a significant death rate due to comorbid conditions. The primary tumor was treated surgically (with or without postoperative radiation) in 363 patients, with survival of 55%, 46%, and 38% at 2, 3, and 5 years, respectively. The tumor was treated primarily with radiation therapy (with or without neck dissection) in 193 patients, with survival of 40%, 33%, and 27% at 2, 3, and 5 years, respectively. Overall survival in the surgical group was better than in the radiation group (P =.005, log-rank chi 2 test). The radiation group was subcategorized into those who underwent radiation because the tumor was so advanced as to be unresectable (n = 86), because they were too unhealthy to undergo radical surgery (n = 23), and because they elected radiation therapy (n = 84). Survival in each of the radiation subgroups at 2, 3, and 5 years was 28%, 20%, and 14%, respectively, in the unresectable group; 34%, 22%, and 11%, respectively, in the unhealthy group; and 57%, 53%, and 46%, respectively, in the elective group. Thus, survival in the elective radiation subgroup exceeded that of the surgical group, although not statistically. We analyzed data regarding T and N stages, age, race, surgical margin status, postoperative radiation therapy, chemotherapy, radiation dose, and tumor site. Multivariate analysis of the surgical group and elective radiation subgroup showed that N stage and age were the strongest predictors of survival and that the method of therapy was not significant. For oropharyngeal cancer, the patients in the elective radiation subgroup did as well as the surgical group. Many patients were noncompliant with portions of therapy, with a resulting reduction in survival. CONCLUSIONS: The data demonstrate the value of analyzing a consecutive series of patients with advanced head and neck cancer. By including patients with comorbidities and those who are noncompliant, we determined a realistic expectation of patient outcomes. By including all patients, the data dramatically show the impact of age, comorbidity, and advanced stage on survival. The survival of patients who underwent elective radiation therapy in combination with neck dissection was similar to that of patients treated with primary tumor surgery. This was particularly true for oropharyngeal tumors. The site and stage-specific data are useful in counseling patients with advanced head and neck cancer regarding treatment choices.

PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses.

A PAX8-PPARgamma rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPARgamma in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPARgamma antibody. PAX8-PPARgamma was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three). Strong, diffuse nuclear immunostaining with the PPARgamma antibody correlated with the presence of PAX8-PPARgamma detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPARgamma were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPARgamma had trabecular growth pattern and thick capsule, but no invasion, and thus may represent "pre-invasive" follicular carcinomas. The absence of PAX8-PPARgamma rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.