The differential diagnosis of dyspnea in a woman with metastatic breast cancer--consideration beyond pulmonary embolism.

Metastatic breast cancer can have protean manifestations. Here we present a case of a woman with recurrent breast cancer who presented with acute dyspnea and evidence of right heart strain. Diagnoses of myocardial ischemia and of pulmonary embolus were ruled out and the patient ultimately succumbed to respiratory failure. At pathology she was found to have tumor emboli clogging capillaries and arterioles, consistent with the diagnosis of embolic carcinomatosis. While a rare diagnosis, clinicians must be aware of this phenomenon in patients with breast cancer who present with rapidly deteriorating pulmonary function.

HHV-8+, EBV+ multicentric plasmablastic microlymphoma in an HIV+ Man: the spectrum of HHV-8+ lymphoproliferative disorders expands.

Human herpesvirus-8 (HHV-8) is associated with several distinct lymphoproliferative disorders: primary effusion lymphoma, multicentric Castleman disease (MCD), MCD-associated plasmablastic lymphoma and HHV-8+, Epstein-Barr virus (EBV)+ germinotropic lymphoproliferative disorder. We report the case of a human immunodeficiency virus (HIV)+ male with fever, generalized lymphadenopathy, and splenomegaly. Two peripheral lymph nodes were excised and showed features of MCD and a prominent proliferation of HHV-8+, EBV+, CD20, CD138, MUM1+, lambda dim+, Ig heavy chain plasmablasts and immunoblasts replacing some follicles. Subsequently, a splenectomy and biopsy of retroperitoneal lymph nodes were performed; the retroperitoneal and splenic hilar lymph nodes showed changes similar to those in the peripheral lymph nodes while the markedly enlarged spleen showed replacement of occasional white pulp by the HHV-8+, EBV+ large cells. The histologic features and coinfection by EBV and HHV-8 suggested a diagnosis of HHV-8+ germinotropic lymphoproliferative disorder. However, the occurrence in an HIV+ individual, the background of MCD, the widespread anatomic distribution and the aggressive clinical course tended to exclude germinotropic lymphoproliferative disorder, and to favor multifocal plasmablastic microlymphoma. The patient died shortly after surgery; postmortem examination showed progression to overt lymphoma. The marrow showed extensive hemophagocytosis, consistent with development of a hemophagocytic syndrome. This unique case has clinical features compatible with a MCD-associated plasmablastic lymphoproliferative disorder, with pathologic features intermediate between HHV-8+ plasmablastic microlymphoma, and HHV-8+ germinotropic lymphoproliferative disorder, although in contrast to both of these, in our case, light chain expression was dim and heavy chain was not detected.

Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features.

Somatic mutations in the epidermal growth factor receptor gene (EGFR) are detected in a subset of lung adenocarcinomas, particularly bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (AWBF), and correlate with clinical response to tyrosine kinase inhibitors (TKIs). In contrast, lung adenocarcinomas refractory to TKIs often have activating mutations in KRAS but lack EGFR mutations. Some adenocarcinomas have mucinous histology, but the clinical and molecular significance of the mucinous pattern is less well studied. We analyzed 43 BAC and AWBF tumors submitted for EGFR mutation testing to identify histopathological features that predicted EGFR or KRAS mutations. EGFR mutations were detected in 14 of 30 (47%) nonmucinous tumors, whereas 0 of 13 mucinous tumors harbored an EGFR mutation (P = 0.003). Missense mutations in KRAS codon 12 were detected in six of seven (86%) mucinous adenocarcinomas but only 3 of 18 (17%) nonmucinous adenocarcinomas (P = 0.003). Thus, in BAC/AWBF mucinous differentiation was significantly correlated with the absence of EGFR mutation and presence of KRAS mutation, suggesting that mucinous BACs/AWBFs are unlikely to respond to TKIs. Therefore, our data suggest that EGFR sequence analysis could be avoided in BAC/AWBF when true mucinous morphology is identified, avoiding the associated testing costs.

Mustard lung secrets: long term clinicopathological study following mustard gas exposure.

Considering the undefinite nature of lung pathology in patients exposed to sulfur mustard (SM) many years after exposure, we conducted this study to document and quantify lung disease in this setting. In a cross sectional study, we selected 23 patients exposed to SM gas approximately 14 years ago during the Iran-Iraq war (1980-1988). We studied their clinical history, physical examination, pulmonary function test (PFT), high-resolution computed tomography scan (HRCT) of the chest, bronchoscopy, and bronchoalveolar lavage (BAL) sampling, and transbronchial lung biopsies. Other potential causes of lung disease, including smoking of cigarettes, were excluded. All 23 patients were symptomatic with cough, dyspnea, and/or felt tight in the chest. All of them had significant air trapping in HRCT and a marked increase of residual volume in PFT. The most common inflammatory cell in BAL fluid was neutrophil (88%). Of the 23 cases, there was sufficient tissue for detailed evaluation in 22. Histologically, 11 cases showed airway epithelial injury, and nine of the 14 lung biopsies with alveoli had histopathological changes diagnosable as organizing pneumonia (OP) or bronchiolitis obliterans OP (BOOP). Two out of 14 cases showed changes suggestive of OP. Inhalation of SM can lead to persistant and clinically significant lung disease, including bronchial mucosal injury and OP, many years after exposure.

Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis.

Genome-wide copy number changes were analyzed in 70 primary human lung carcinoma specimens and 31 cell lines derived from human lung carcinomas, with high-density arrays representing approximately 115,000 single nucleotide polymorphism loci. In addition to previously characterized loci, two regions of homozygous deletion were found, one near the PTPRD locus on chromosome segment 9p23 in four samples representing both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) and the second on chromosome segment 3q25 in one sample each of NSCLC and SCLC. High-level amplifications were identified within chromosome segment 8q12-13 in two SCLC specimens, 12p11 in two NSCLC specimens and 22q11 in four NSCLC specimens. Systematic copy number analysis of tyrosine kinase genes identified high-level amplification of EGFR in three NSCLC specimens, FGFR1 in two specimens and ERBB2 and MET in one specimen each. EGFR amplification was shown to be independent of kinase domain mutational status.

Pathogen discovery from human tissue by sequence-based computational subtraction.

We have recently reported a new pathogen discovery approach, "computational subtraction". With this approach, non-human transcripts are detected by sequencing cDNA libraries from infected tissue and eliminating those transcripts that match the human genome. We show now that this method is experimentally feasible. We generated a cDNA library from a tissue sample of post-transplant lymphoproliferative disorder (PTLD). 27,840 independent cDNA sequences were filtered by computational subtraction against the known human sequence to identify 32 nonmatching transcripts. Of these, 22 (0.1%) were found to be amplifiable from both infected and noninfected samples and were inferred to be human DNA not yet contained in the available human genome sequence. The remaining 10 sequences could be amplified only from Epstein-Barr virus (EBV)-infected tissues. All 10 corresponded to the known EBV sequence. This proof-of-principle experiment demonstrates that computational subtraction can detect pathogenic microbes in primary human-diseased tissue.