Diffuse malignant mesothelioma and synchronous lung cancer: A clinicopathological study of 18 cases.

OBJECTIVES: To examine the clinicopathologic characteristics of individuals with diffuse malignant mesothelioma (DMM) occurring concurrently with lung cancer (LC). MATERIALS AND METHODS: A database of approximately 3800 patients with DMM was reviewed, from which 18 patients (0.5%) who had synchronous LC were identified. The clinicopathologic features, as well as the occupational exposure history and fiber burden analysis data were examined. RESULTS: The patient median age was 68 years (range 58-84 years). Of the 18 patients (14 male, 4 female), 11 (61%) had epithelial, 5 (28%) had biphasic, and 2 (11%) had sarcomatoid DMM, with the majority (16 cases; 89%) originating in the pleura and only 2 were peritoneal. Among the histologic types of LC, adenocarcinoma was most frequent (12 cases; 67%), while 5 cases of squamous cell carcinoma, and 1 case of small cell carcinoma were observed. Three patients also had a history of prior malignancy (1 with testicular seminoma and bladder carcinoma and 2 with prostate carcinoma). Fifteen patients had a positive smoking history. All but 3 had documented asbestos exposure. Three had histologic features of asbestosis. Mineral analysis performed in 8 showed an elevated asbestos fiber burden in 4 (22%). Amosite was detected in 4 patients, crocidolite in 3, and non-commercial amphiboles in 5. CONCLUSION: The finding of simultaneous carcinoma of the lung and DMM is distinctly unusual. The majority of patients are male smokers with pleural epithelial DMM and lung adenocarcinoma. This study represents the largest cohort of patients reported to date with synchronous malignant mesothelioma and lung cancer, and we propose guidelines for making a diagnosis of synchronous malignant mesothelioma and primary lung cancer.

Malignant (Diffuse) Mesothelioma in Patients With Hematologic Malignancies: A Clinicopathologic Study of 45 Cases.

CONTEXT: Ionizing radiation has a role in the development of malignant mesothelioma, in several epidemiologic studies, including patients with hematologic malignancies. OBJECTIVE: To study the clinicopathologic characteristics of patients with malignant mesothelioma and hematologic malignancies with and without a history of radiotherapy. DESIGN: From a database of approximately 3600 patients with malignant mesothelioma, we identified 45 patients (1%) who also had hematologic malignancies. We examined clinicopathologic features and noted whether the patient had received radiotherapy for malignancy, comparing those with and those without such exposure. RESULTS: Among the 45 cases, 18 (40%) had Hodgkin lymphoma, 15 (33%) had non-Hodgkin lymphoma, 10 (4%) had chronic lymphocytic leukemia, and 2 (22%) had chronic myelogenous leukemia; 20 patients (44%) had a history of radiotherapy, and 23 (51%) did not. Most patients with Hodgkin lymphoma (16 of 18; 90.0%) received radiation, whereas none of the patients with leukemia (0 of 12) and only 20% (3 of 15) of the patients with non-Hodgkin lymphoma did so. Patients without radiation were older than patients who received radiotherapy (median, 73 versus 54 years, respectively; P < .001), had a shorter interval from diagnosis of hematologic malignancy to that of mesothelioma (median, 2 versus 24 years, respectively; P < .001), and had a shorter survival period (median, 6.0 versus 14.0 months, respectively; P = .02). Epithelial mesotheliomas were proportionately more common in patients with a history of radiotherapy. CONCLUSIONS: Patients with mesothelioma and hematologic malignancies with a history of radiation tended to be younger, had a longer interval from diagnosis of hematologic malignancy to that of mesothelioma, had a longer survival period, and were more likely to have the epithelial variant compared with patients without radiotherapy.

Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases.

Sarcomatoid mesothelioma is the least common, but most aggressive of the three major histological types of mesotheliomas. This study comprises 326 cases of sarcomatoid mesotheliomas among 2000 consecutive malignant mesothelioma cases received in consultation (16%). Patients included 312 men (96%) and 14 women (4%), with a median age of 70 years (range 41-94 years). Most tumors were pleural (319; 98%), and 7 were peritoneal (2%). Some desmoplastic features were identified in 110 cases (34%), and 70 (21%) were classified as desmoplastic. Rare subtypes included two cases with a lymphohistiocytoid pattern (<1%) and eight heterologous mesotheliomas (2%). Labeling for cytokeratins (CKs) was observed in 261/280 cases (93%), and for calretinin and vimentin in 31 and 91%, respectively. Pleural plaques were present in 79% of cases for which information was available, and asbestosis was diagnosed in 34/127 cases (27%). Median survival was 3.5 months. Fiber analysis was performed in 61 cases. The median asbestos body count was 1640/g wet lung tissue (by light microscopy). Amosite fibers were the most commonly identified fibers using energy-dispersive X-ray analysis and were significantly higher in the sarcomatoid cases, as were uncoated fibers using scanning electron microscopy. This study represents the largest series of sarcomatoid and desmoplastic malignant mesotheliomas to date and confirms the diagnostic usefulness of CK immunohistochemistry. The relationship with asbestos exposure--particularly amosite--and an association with pleural plaques and less often asbestosis is confirmed.

Topoisomerase II alpha status in renal medullary carcinoma: immuno-expression and gene copy alterations of a potential target of therapy.

PURPOSE: Renal medullary carcinoma is an aggressive renal neoplasm without currently available effective therapy to our knowledge. Topoisomerase II alpha is a gyrase involved in cell proliferation, and DNA maintenance and repair. Topoisomerase II alpha is a target of inhibiting agents such as anthracyclines. Triggered by a recent response to topoisomerase II alpha inhibitors in a patient with renal medullary carcinoma, we evaluated topoisomerase II alpha expression in relation to the proliferation index and topoisomerase II alpha gene copy number status in a larger series of patients with renal medullary carcinoma. MATERIALS AND METHODS: Archival tissues from 14 renal medullary carcinomas were retrieved from our 3 institutions. Immunohistochemistry was performed using monoclonal antibodies for topoisomerase II alpha and Ki67. The percent of cells with positive nuclear staining was assessed in the highest area of expression for each marker. A previously suggested greater than 5% cutoff was used for topoisomerase II alpha over expression. The topoisomerase II alpha gene copy number was evaluated using fluorescence in situ hybridization. Locus specific topoisomerase II alpha gene and chromosome 17 centromere probes were used. The total number of topoisomerase II alpha and chromosome 17 centromere signals was counted in 150 cells per tumor and a topoisomerase II alpha-to-chromosome 17 centromere signal ratio was calculated in each tumor. A topoisomerase II alpha-to-chromosome 17 centromere ratio of 2.0 or greater and less than 0.8 was used as a cutoff for amplification and deletion, respectively. The percent of tumor cells with polysomic, eusomic or monosomic chromosome 17 status was also determined. RESULTS: On immuno-expression analysis topoisomerase II alpha immunohistochemistry was technically inconclusive in 1 renal medullary carcinoma. Topoisomerase II alpha was over expressed in 11 of 13 renal medullary carcinomas (85%) (median 50%, range 1% to 80%). As expected, a high Ki67 proliferation index was noted in 13 of 14 tumors (median 87.5%, range 2% to 100%). Ki67 expression was greater than topoisomerase II alpha expression in all 13 informative tumors. A strong, statistically significant correlation was found for topoisomerase II alpha and Ki67 expression (pairwise CC 0.9, p = 0.0000). Topoisomerase II alpha over expression was associated with shorter survival (p = 0.000). On fluorescence in situ hybridization no topoisomerase II alpha amplification was detected in any of the 14 renal medullary carcinomas, including the 11 with topoisomerase II alpha over expression. Topoisomerase II alpha gene deletions were noted in 4 tumors. Two of 4 deletions were associated with chromosome 17 monosomy and 2 were in eusomic chromosome 17 tumors. CONCLUSIONS: Topoisomerase II alpha is over expressed in 85% of renal medullary carcinomas, potentially supporting the use of topoisomerase II alpha inhibitor agents to treat this aggressive renal tumor. Our findings suggest that topoisomerase II alpha over expression in our renal medullary carcinoma cohort was not due to gene amplification, but rather to transcriptional or post-transcriptional modifications. The significance of the incidentally found topoisomerase II alpha deletions in 28% of renal medullary carcinomas requires further evaluation.

An unusual case of recurrent hyperparathyroidism and papillary thyroid cancer.

OBJECTIVE: To report an unusual occurrence of recurrent hyperparathyroidism due to papillary thyroid carcinoma. METHODS: We describe the clinical history, physical examination findings, laboratory values, imaging findings, and pathologic findings of a woman who developed recurrent hyperparathyroidism 13 years after successful parathyroidectomy. RESULTS: A 59-year-old woman presented to our clinic with recurrent primary hyperparathyroidism. In 1994, she presented with nephrolithiasis and underwent resection of a right superior parathyroid adenoma that resulted in clinical and biochemical cure. Her clinical course had been followed at periodic intervals, and she had been symptom-free and normocalcemic. In 2007, she again developed nephrolithiasis and was documented to have recurrent hyperparathyroidism. Imaging studies suggested a parathyroid adenoma near the right inferior pole of the thyroid. The patient had reoperative neck exploration. No obvious parathyroid adenoma was found and a right thyroid lobectomy was performed, which resulted in normalization of intraoperative intact parathyroid hormone levels, and the incision was closed. Final pathology demonstrated no parathyroid adenoma, but instead, a 1-cm papillary thyroid carcinoma that stained positive for parathyroid hormone. More than 6 months after surgery, she remains clinically and biochemically cured. CONCLUSIONS: Recurrent hyperparathyroidism occurs secondary to multiple causes. This case demonstrates the challenge a surgeon faces in managing recurrent disease and highlights a rare phenomenon of papillary thyroid cancer causing recurrent hyperparathyroidism.

Toll-like receptor 4-dependent responses to lung injury in a murine model of pulmonary contusion.

Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 (TLR-2) participates in the inflammatory response to lung injury. We hypothesized that the TLR-4, in an MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function, pulmonary neutrophil recruitment, and the systemic innate immune response. Comparisons were made between wild-type mice and mice deficient in TLR-4 or MyD88. We found TLR-4-dependent responses to pulmonary contusion that include hypoxemia, edema, and neutrophil infiltration. Increased expression of IL-6 and chemokine (C-X-C motif) ligand 1 in the bronchoalveolar lavage and serum was also dependent on TLR-4 activation. We further demonstrated that these responses to pulmonary contusion were dependent on MyD88, an adapter protein in the signal transduction pathway mediated by TLRs. These results show that TLRs have a primary role in the response to acute lung injury. Lung inflammation and systemic innate immune responses are dependent on TLR activation by pulmonary contusion.

Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion.

Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We report that Toll-like receptor (TLR) 2 participates in the inflammatory response to lung injury. To show this, we use a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans based on histologic, morphologic, and biochemical criteria of acute lung injury. The inflammatory response to pulmonary contusion in our mouse model is characterized by pulmonary edema, neutrophil transepithelial migration, and increased expression of the innate immunity proinflammatory cytokines IL 1beta and IL 6, the adhesion intracellular adhesion molecule 1, and chemokine (CXC motif) ligand 1. Compared with wild-type animals, contused Tlr2(-/-) mice have significantly reduced pulmonary edema and neutrophilia. These findings are associated with decreased levels of circulating chemokine (CXC motif) ligand 1. In contrast, systemic IL 6 levels remain elevated in the TLR2-deficient phenotype. These results show that TLR2 has a primary role in the neutrophil response to acute lung injury. We suggest that an unidentified noninfectious ligand generated by pulmonary contusion acts via TLR2 to generate inflammatory responses.

Recurring translocation (10;17) and deletion (14q) in clear cell sarcoma of the kidney.

CONTEXT: Clear cell sarcoma of the kidney (CCSK) is a prognostically unfavorable renal neoplasm of childhood. Previous cytogenetic studies of CCSK have reported balanced translocations t(10;17)(q22;p13) and t(10;17)(q11;p12). Although the tumor suppressor gene p53 is located at the chromosome 17p13 breakpoint, p53 abnormalities are rarely present in these tumors. OBJECTIVE: To identify cytogenetic abnormalities in CCSK and correlate these findings with other clinicopathologic parameters. DESIGN: A retrospective review of CCSK patients from 1990 to 2005 was conducted at our medical center. We performed clinical and histologic review, p53 immunohistochemical and classic cytogenetics (or ploidy analysis), and p53 fluorescence in situ hybridization analyses. RESULTS: Five male patients (age range, 6 months to 4 years) were identified with cytogenetic abnormalities. Of 3 cytogenetically informative cases, one revealed a clonal balanced translocation t(10;17)(q22;p13) and an interstitial deletion of chromosome 14, del(14)(q24.1q31.1), and the other 2 patients had normal karyotypes. Fluorescence in situ hybridization for p53 in the t(10;17) case revealed no deletion. Immunohistochemical evaluation of p53 demonstrated lack of nuclear protein accumulation in all cases. CONCLUSIONS: Together with the published literature, our results indicate that translocation (10;17) and interstitial deletions of chromosome 14q are recurring cytogenetic lesions in CCSK. To date, 3 cases of CCSK or "sarcomatoid Wilms tumors" have been reported to exhibit t(10;17). One previously reported case of CCSK contained deletion 14q. Results of p53 immunohistochemistry and/or p53 fluorescence in situ hybridization in this report suggest lack of mutations or deletions of this tumor suppressor in these CCSK cases. The t(10;17) breakpoint and deletion of chromosome 14q24 suggest that other genes are involved in tumor pathogenesis.

Diagnostic pitfalls associated with fine-needle aspiration biopsy in a patient with the myxoid variant of monophasic fibrous synovial sarcoma.

Synovial sarcoma (SS) is one of the most common soft tissue tumors that typically presents in the extremities of young adults, but may occur at any site and affect children during the first decade. Herein we discuss a 12-yr-old male who complained of left foot pain and plantar mass. A fine-needle aspiration biopsy of an 8 cm subcutaneous mass was performed revealing a myxoid spindle cell neoplasm. The cytologic differential diagnosis included a myxoid neurofibroma, neurothekeoma, and a myxoid sarcoma. Subsequent excision of the mass revealed a monophasic fibrous SS with myxoid features. Examination of the tissue by fluorescence in situ hybridization confirmed the presence of characteristic SS SYT gene rearrangement at chromosome 18q11.2. This case underscores that the cytologic distinction of mxyoid spindle cell tumors may be challenging. We report the cytologic features of a myxoid monophasic fibrous SS, and discuss its distinction from other benign and malignant myxoid soft tissue neoplasms.

The pathogenesis of pulmonary contusion: an open chest model in the rat.

BACKGROUND: Chemokines direct leukocytes to areas of inflammation or injury. In general, CC chemokines (MCP-1, MIP-1alpha, RANTES) are chemoattractants for mononuclear cells and CXC (CINC-1, MIP-2alpha) for polymorphonuclear cells (PMNs). Herein we describe an open chest model of pulmonary contusion (PC) in a rodent (rat) and have identified a possible role for CC and CXC chemokines in the pathogenesis of PC. METHODS: Sprague-Dawley rats (350 g) underwent thoracotomy. The exposed lung was struck with a piston at 5.2 m/s (150 J/M2). Blood, bronchoalveolar lavage (BAL), and lung tissue were collected at 3 hours and 24 hours after injury. PaO2/FiO2 (P/F) ratio was calculated at 15-minute intervals for 3 hours after contusion. Serum was evaluated for cytokine and chemokine expression using ELISA. Cell count/differential was performed on BAL, and lung tissue was obtained for histologic analysis, protein expression and wet to dry weights. Data are reported as pg/mL +/- SE. Data were analyzed using Student's t test to identify significant differences (p < or = 0.05 significant) between sham and injured animals. RESULTS: Piston impact caused PC based upon morphologic and histologic criteria. BAL cell count and lung wet to dry weights were increased and P/F ratio was decreased after PC. Systemic levels of IL-ra, MCP-1, and the CXC chemokines MIP-2alpha and CINC-1 were significantly elevated at 3 hours when sham and injured animals were compared. All chemokines were found to be significantly elevated at 24 hours, consistent with the early PMN and subsequent mononuclear infiltration observed in the contused lung. Pulmonary expression of TNF-alpha, IL-1beta, CINC-1, MIP-2alpha, ICAM-1, and elastase were increased and activated systemic neutrophils showed increased CD-11b. CONCLUSION: A model of PC is described in which innate inflammation is activated locally and systemically. Systemic levels of CC and CXC chemokines are increased after PC. This correlates with elevated PMN CD-11b expression, enhanced pulmonary ICAM-1 expression, and mononuclear and PMN infiltration into the lung and alveolar space. Elevated levels of CC and CXC chemokines are seen after PC and may be involved in the lung's inflammatory response to injury.

Functional and gene expression analysis of the p53 signaling pathway in clear cell sarcoma of the kidney and congenital mesoblastic nephroma.

Mutation of p53 has been implicated in progression of classical Wilms tumor (WT) into the anaplastic variant (AWT), drug resistance, and poor prognosis. Because of prognostic similarities, clear cell sarcoma of the kidney (CCSK) has been classified with AWT and other aggressive pediatric renal tumors, apart from congenital mesoblastic nephroma (CMN), which is instead a relatively benign tumor of neonates. Initially, CCSK and CMN were assumed to be ontologically related, but the role of p53 in the pathogenesis of either disease has not been sufficiently evaluated as in AWT. We examined the status of p53 in CMN and CCSK in comparison to AWT by immunohistochemistry and mRNA analysis of p53, the downstream effector p21(WAF-1/CIP-1) ( p21), the multidrug resistance gene MDR-1, a putative target of p53, and the p53-antagonist Mdm-2. Surprisingly, strong p53 nuclear immunoreactivity was found in cultures from two CMN specimens, but not in frozen or fixed tumor tissue from five other CMN specimens, nor in cell lines or tumor tissue from CCSK. Sequence analysis excluded p53 mutations. The size of the p53 mRNA in CMN and CCSK primary tumors excluded gross deletions or rearrangements. Low levels of Mdm-2 mRNA in CCSK and CMN primary tumors and cultures did not support a role for Mdm-2. Absence of MDR-1 mRNA excluded MDR-1 in the drug-resistant phenotype of CCSK. Cisplatin-induced p21 transactivation assays and G(1) cell cycle arrest analyses showed that p21 transactivation and G(1) arrest occurred in both CCSK and CMN cultures, demonstrating integrity of the p53 signal transduction pathway. Absence of p53 functional abnormalities excluded relationships between CCSK and CMN as in AWT, supporting the association of cellular CMN with congenital fibrosarcomas as more recently proposed.