José Javier Gómez-Román

Human herpesvirus-8 genes are expressed in pulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor).

The presence of human herpesvirus-8 DNA sequences, as well as an overexpression of human interleukin-6 and human cyclin D1 in myofibroblastic cells of inflammatory myofibroblastic tumor (inflammatory pseudotumor), has recently been reported. We describe the pattern of human herpesvirus-8 gene expression in five cases of pulmonary inflammatory myofibroblastic tumor. Reverse transcriptase–polymerase chain reaction (RT-PCR), with several positive and negative controls, was performed to detect mRNA of 11 open reading frames encoded by human herpesvirus-8 in lytic and latent stages of viral replicative cycle. We found molecular transcripts from ORF16, ORFK13, and ORF72 in the five cases and from ORFK2 in four of five neoplasms. The corresponding encoded proteins were human homologous oncoproteins (viral cyclin-D), inflammatory cytokines (viral IL-6), and inhibitors of apoptotic pathways (viral FLIP and viral Bcl-2), mostly expressed in a latent viral replicative stage. The rest of open reading frames examined included mainly lytic-associated genes and showed no expression. The spectrum of expressed viral genes is not the same as can be observed in Kaposis sarcoma or multicentric Castlemans disease, suggesting that human herpesvirus-8 plays a different role in the pathogenesis of its associated diseases. These differences may be related to either cell-specific or immunologic host factors.

Presence of human herpesvirus-8 DNA sequences and overexpression of human IL-6 and cyclin D1 in inflammatory myofibroblastic tumor (inflammatory pseudotumor).

Inflammatory myofibroblastic tumor (IMT) is composed of myofibroblasts, plasma cells, and lymphocytes. Cytokines are possibly involved in its pathogenesis. Human herpesvirus-8 (HHV-8) encodes cell cycle regulatory and signaling proteins. A combination of nested PCR with several negative controls and Southern blot methods showed the presence of HHV-8 DNA in seven cases of IMT. Additionally, strong expression was demonstrated by in situ hybridization in many tumoral nuclei. Most of the myofibroblasts in all of the cases were immunoreactive for human IL-6 and cyclin D1. These cytokines probably have a paracrine action and may sustain myofibroblastic growth. HHV-8 could play an essential role in triggering IMT development by a local reactivation of viral lytic replication. The relationship between HHV-8 and immunosuppression status as the only associated cause for tumorigenesis should be revised.

Everolimus-related pulmonary toxicity in heart transplant recipients.

Pulmonary toxicity (PT) is emerging as a frequent and serious complication of sirolimus, a proliferation signal inhibitor (PSI) used in solid-organ transplantation. Everolimus is a more recently developed PSI with molecular structure very similar to that of sirolimus. Surprisingly, although experience with everolimus is increasing and becoming substantial, there remains very little information about everolimus-related PT. Herein we report 2 heart transplant recipients who developed a non-infectious pulmonary syndrome after everolimus treatment was started. Transbronchial pulmonary biopsy specimens showed typical interstitial pneumonitis, and everolimus discontinuation resulted in rapid clinical and radiological improvement. Although PT seems to be more common after sirolimus exposure, everolimus is by no means spared from this potentially lethal complication and should always be suspected in the relevant clinical setting.

A type-specific study of human papillomavirus prevalence in cervicovaginal samples in three different Spanish regions

Human papillomavirus (HPV) is the most frequent sexually transmitted viral infection. It is necessary to know HPV genotype distribution to identify how many women will be protected by HPV vaccines. During a period of 18 months, we have analyzed 2362 HPV positive reporting data from a secondary demand screening program in three regions in Spain (Cantabria, Leon and Burgos). The study has been conducted using polymerase chain reaction and tube array hybridization covering the 35 HPV genotypes described as affecting anogenital mucosa. There were no significant differences between the three regions according to genotype distribution. The most frequent were HPV16 (19.18%), HPV53 (11.26%) and HPV58 (7.66%). HPV18 was the source of 4.02% of infections. High‐risk HPVs were found in 1863/2362 cases. HPV16 was present in 24.3% of high‐risk infections and HPV18 was found in 5.1%. Uncommon genotypes (<5% of the total prevalence each) were found in 17,9% of the total high‐risk infections (334/1863). Multiple infections were diagnosed in 22% of the cases. The HPV genotype distribution is different from previously published data when multiple types are included in the screening. Both HPV16/18 account for 30% of high‐risk infections in a clinical setting in Spain. The presence of multiple genotypes is very common among the population.

Simultaneous Multiorgan Presence of Human Herpesvirus 8 and Restricted Lymphotropism of Epstein-Barr Virus DNA Sequences in a Human Immunodeficiency Virus—Negative Immunodeficient Infant

Because a profound dysregulation of the immune system occurs in primary immunodeficiencies, viral infections are not uncommon. Human herpesvirus (HHV)-8 DNA was detected by polymerase chain reaction (PCR) analysis, Southern blotting, and in situ hybridization (ISH) in peripheral blood mononuclear cells and lymphoid organs (bone marrow, spleen, and lymph nodes) and endothelial and epithelial cells and macrophages from several organs (skin, lung, esophagus, intestine, choroid plexus [but not in brain or cerebellum], heart, striated muscle, liver, and kidney) of a human immunodeficiency virus-negative infant with DiGeorge anomaly who died of disseminated infection. Epstein-Barr virus DNA sequences were detected in the spleen and lymph nodes (by PCR and ISH) and in bone marrow (only by ISH) but not in blood or nonlymphoid organs. This report is believed to be the first of multiorgan dissemination of HHV-8 in a primary immunodeficiency.

Hemorragias alveolares difusas pulmonares

Las hemorragias alveolares difusas son cuadros clinicos que pueden ser catastroficos si no se diagnostican y tratan a tiempo. Suelen estar causadas en gran parte por vasculitis de vasos pequenos pulmonares. Existen 3 grandes grupos: a) las pauciinmunitarias, generalmente asociadas a capilaritis y anticuerpos citoplasmicos antineutrofilos; b) las producidas por depositos inmunologicos, que pueden detectarse mediante inmunofluorescencia, y c) un gran grupo miscelaneo, que incluye toxicidad por farmacos, infecciones y causas idiopaticas. El diagnostico se basa en la integracion de signos, sintomas, estudios serologicos y morfologicos. Se debe recomendar la realizacion de una biopsia por videotoracoscopia en los pacientes con hemorragia alveolar difusa de causa inexplicada, sin un diagnostico previo de enfermedad sistemica, en la que los estudios serologicos no proporcionan datos concluyentes, y en general en aquellos pacientes con un elevado indice de sospecha de que esten desarrollando una hemorragia alveolar difusa. En todos estos casos, la biopsia debe remitirse en fresco a los servicios de anatomia patologica para permitir la congelacion de un fragmento tisular, que sera utilizado para el estudio por inmunofluorescencia.

Epstein-Barr virus-associated adenocarcinomas and squamous-cell lung carcinomas.

The association of Epstein–Barr virus with pulmonary neoplasms has been restricted to lymphoepithelioma-like carcinomas in Asian patients. We have selected 19 pulmonary adenocarcinomas and squamous-cell carcinomas from 1545 pulmonary neoplasms diagnosed from 1996 to 2007 in an occidental population. All of them showed a low-power appearance confusing between an epithelial and a lymphoid neoplasm, with a dense lymphocytic infiltrate intermingled with neoplastic cells giving an image akin to lymphoepithelial complexes. Five carcinomas presented typical features of Lymphoepithelioma-like lung carcinomas; but six cases could be classified as squamous-cell carcinomas and eight as adenocarcinomas. A semiquantitative polymerase chain reaction method, Early RNA genes 1 and 2 in situ hybridization as well as Latent membrane protein immunostaining for Epstein–Barr virus DNA, RNA and protein detection methods were used in every case. None of Lymphoepithelioma-like carcinomas showed positivity for Epstein–Barr virus in any used method. Otherwise four squamous-cell carcinomas and eight adenocarcinomas (12 cases) demonstrated viral sequences in polymerase chain reaction and/or in situ hybridization analysis in neoplastic cells. Moreover two adenocarcinomas also displayed human herpesvirus 6 DNA sequences coamplification in molecular analysis. Protein immunostaining was focally positive in only three cases. We performed the same analysis in 70 more cases of conventional pulmonary squamous-cell carcinomas and adenocarcinomas that gave negative results. In conclusion, a subset of pulmonary squamous-cell carcinomas and adenocarcinomas show Epstein–Barr DNA and/or RNA sequences in neoplastic cells. This finding expands the spectra of epithelial cell common tumours Epstein–Barr virus associated.

Primary lymphoplasmacytoid lymphoma of the trachea with immunoglobulin G paraprotein.

A primary tracheal lymphoma with immunoglobulin G (IgG)‐associated monoclonal serum paraprotein treated with surgery and chemotherapy is reported. As far as we know this is the first lymphoplasmacytoid lymphoma reported in the tracheobronchial tree and the first with a serum and tissue IgG monoclonal paraprotein. Differential diagnosis must be made essentially with extramedullary plasmacytoma and mucosa‐associated lymphoid tissue lymphoma. CD‐45RB strong positivity and the absence of lymphoepithelial lesions may help to differentiate lymphoplasmacytoid lymphoma from them. We expand the spectrum of lymphoid lesions with plasmacytoid features that can occur in the tracheobronchial tract.

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage is a clinical syndrome that can be life threatening if not diagnosed and treated in time. In most cases it occurs largely as a result of small-vessel vasculitis of the lungs. The many different forms can be classified into 3 large groups: a) pauciimmune disease, which generally involves pulmonary capillaritis and is associated with the presence of antineutrophil cytoplasmic antibodies; b) syndromes caused by immune deposits, which can be detected by immunofluorescence; and c) a large miscellaneous group that includes drug reactions, infections, and idiopathic disease. Diagnosis is based on a combination of signs, symptoms, serology, and histology. Biopsy with video-assisted thoracoscopy should be recommended in patients with diffuse alveolar hemorrhage without known cause and with no prior diagnosis of systemic disease, in whom serology studies do not reveal conclusive data, and in general in those patients for whom there is a high level of suspicion of diffuse alveolar hemorrhage. In all such cases, the fresh biopsy material should be sent to the pathology laboratory for preparation of frozen sections to be used for immunofluorescence.

Anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma presenting as a bladder neoplasm

Malignant lymphoma presenting in the bladder has been classified in primary cases, as the first sign of disseminated disease and as a secondary infiltration. Most of the examples in the literature have been reported as single cases. Reported herein is the case of a 45‐year‐old man with an anaplastic large cell lymphoma (anaplastic lymphoma kinase (ALK) and granzyme B positive) that presented as a bladder neoplasm. The morphological differential diagnosis was complex because the EMA‐positive immunophenotype, CD45 and CD3 negativity and the clinical manifestation simulated a transitional cell carcinoma. It is important to be aware of its existence because a poorly differentiated bladder carcinoma cannot be ruled out if CD30 and ALK immunostaining are not performed. T‐cell receptor‐γ clonal rearrangement could be also helpful in these cases. Although bladder involvement by recurrent lymphoma is a sign of widely disseminated disease and it is associated with a very poor prognosis, it seems that chemotherapeutic regimens in this kind of ALK‐positive lymphoma could be effective, given that the present patient had an impressive response to chemotherapy treatment.