Inflammatory Myofibroblastic Tumor After Lung Transplant-A Rare and Aggressive Complication: A Case Report.

INTRODUCTION: Malignant diseases are well-known complications after lung transplantation (LT). Among these, inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with a not well-known and often aggressive biological behavior. MATERIAL AND METHODS: We hereby describe 2 cases of cystic fibrosis patients who underwent bilateral sequential LT (BSLT) complicated by IMT. RESULTS: A 26-year-old man presented a right endobronchial lesion 6 months after BSLT. Two consecutive fiber bronchoscopic biopsies showed granulation tissue. For the persistent lesion growth, the patient underwent a transthoracic biopsy showing histologic diagnosis of IMT. Therefore, he underwent to right pneumonectomy that was unfortunately complicated after 6 months with a late bronchopleural fistula and empyema with exitus 6 months later. A 31-year-old woman 1 year after BSLT presented with a left voluminous pleural-parenchymal lesion; the histologic examination after biopsy revealed an IMT. She underwent a removal of the lesion with a macroscopic R0 resection. Histologic, immunophenotypic, and cytogenetic examinations showed a strong overexpression of anaplastic lymphoma kinase requiring biological adjuvant therapies; however, the patient refused it. Four years later, she presented a recurrence treated with debulking procedure and adjuvant radiotherapy. At last follow-up, the patient was alive with stable disease and optimal graft function. CONCLUSIONS: Although IMT is a rare complication after lung transplant, to obtain a careful diagnosis, an early and aggressive treatment is mandatory.

Case report of anti-transcription intermediary factor-1-γ/α antibody-positive dermatomyositis associated with gastric cancer and immunoglobulin G4-positive pulmonary inflammatory pseudotumor.

Dermatomyositis is a rare connective tissue disease often associated with internal malignancy and interstitial pneumonitis. Serologically, various auto-antibodies (Ab) are associated with dermatomyositis. Anti-transcription intermediary factor-1-γ/α (TIF-1-γ/α) Ab was recently identified as an auto-Ab and was observed mostly in cancer-associated dermatomyositis. IgG4-related disease is a newly described entity characterized by increased serum IgG4 levels and IgG4-positive plasma cell infiltration with fibrosis in organs such as the pancreas and parotid gland. IgG4-related disease also includes inflammatory pseudotumors in various organs. We report herein a 59-year-old Japanese man who had dermatomyositis complicated with a gastric cancer and an IgG4-related pulmonary inflammatory pseudotumor. He manifested typical classical Gottron's papules on the fingers, V-sign erythema on the chest, flagellate erythema on the back, nail fold bleeding and facial erythema. Serum levels of anti-TIF-1-γ/α Ab were positive as assessed by immunoprecipitation assay. He also had bilateral swelling of the parotid gland, and an excised specimen of the lung showed inflammatory pseudotumor with IgG4-positive plasma cells. As far as we know, this case is the first to report the association of IgG4-related disease and TIF-1-γ/α-positive dermatomyositis. Further accumulation of such cases is required to elucidate the mechanism of this association.

[Immunoglobulin G4-related inflammatory pseudotumor of the lung].

A 61-year-old man was pointed out a solitary nodule located in the left lung (S9) measuring 18 × 29 mm in size along with lymphadenopathy by chest computed tomography (CT). Positron emission tomography( PET) scan showed a positive sign corresponding to the nodule[ standardized uptake value (SUV) max 5.8]. No diagnostic material was obtained from the transbronchial tumor biopsy, since it was difficult to rule out malignancy, surgical biopsy was performed with sampling of mediastinal lymph nodes. Histopathological examination showed marked infiltration of inflammatory cells, many of which were demonstrated to be immunoglobulin (Ig) G4-positive plasma cells by immunohistochemical staining. Hence, IgG4-related inflammatory pseudotumor of the lung was diagnosed.

Immunoglobulin G4-related inflammatory pseudotumor of the lung.

An 82-year-old man presented with a nodule in the right S(2)a of the lung as seen by chest computed tomography (CT). He had undergone treatment for chronic obstructive lung disease. He had a 53-year history of smoking 20 cigarettes a day. Subsequent to the appearance of the nodule in the right S(2)a, the CT images revealed consolidations in the right S(2)b, right S(3), and left S(5). The nodule in the right S(2)a was diagnosed as squamous cell carcinoma after performing video-assisted thoracoscopic wedge resection of the lung. After 4 months, the size of the consolidation in the right S(2)b increased. Recurrence of lung cancer was suspected. Using transbronchial lung biopsy, the consolidation in the left S(5) was diagnosed as organizing pneumonia; therefore, right upper lobectomy was performed. The consolidations in the right S(2)b and right S(3) were diagnosed as inflammatory pseudotumors with infiltrations of immunoglobulin G4-positive plasma cells.

Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells.

Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty-five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (> or =5 switched memory B cells/mL, n = 21). CD3(+) T-cell counts and CD19(+) B-cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.

Presence of immunoglobulin heavy chain rearrangement in so-called "plasma cell granuloma of the lung".

Inflammatory pseudotumor of the lung appears to be a set of heterogeneous disorders. Histologically, three subtypes of pulmonary IPTs have been delineated. Among these, plasma cell granuloma (PCG) is characterized by prominent lymphoplasmacytic infiltration, and PCG has been added to the list of differential diagnostic problems of mucosa-associated lymphoid tissue (MALT) type lymphoma. To investigate the presence or absence of monoclonal B-cell proliferation, we analyzed the immunohistological and genotypic findings in three cases of pulmonary PCGs. Histologically, the three lesions were characterized by severe infiltration of mature plasma cells, plasmacytoid cells, and small lymphocytes intermixed. Scattered Russell bodies (intracytoplasmic inclusions) were present in all three cases, but there were no Dutcher bodies (intranuclear inclusions) or centrocyte-like cells. Immunohistochemical studies of light chain determinants demonstrated the polytypic nature of B-cells. There was no CD5(+), CD43(+) or cyclin D1(+) B-lymphocytes in any of the three lesions. There were no lymphoepithelial lesions detected within any of the three lesions even by immunostaining for cytokeratin. However, polymerase chain assay for immunoglobulin heavy chain gene demonstrated a clonal band in one of the three cases. It currently remains unclear whether this one case, demonstrating IgH gene rearrangement in our series, could be a sign of the prelymphomatous stage (e.g. incipient MALT type lymphoma) or merely represents an exaggeration of normal B-cell clonal response.

IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung.

The association between IgG4 dysregulation and inflammatory pseudotumor (IPT) was first reported in sclerosing pancreatitis. Recently, we described IPTs of the liver and breast, into both of which many IgG4-positive plasma cells had infiltrated. In this study, we examined the clinical and histological features of 9 cases of IPT (histologically corresponding to plasma cell granuloma) of the lung with an emphasis on IgG4-positive plasma cell infiltration. The lesions were characterized histologically by dense lymphoplasmacytic infiltrates intermixed with fibrosis and, in some cases, prominent eosinophilic infiltration, irregular narrowing of bronchioles entrapped in nodules, and an interstitial pneumonia pattern at the boundaries of nodules. Obliterative phlebitis was easily found in all cases, and 5 lesions also had obliterative arteritis. Immunostaining revealed many IgG4-positive plasma cells diffusely distributed within nodules, and the ratios of IgG4-positive to other plasma cells were extraordinarily high. Of the 9 patients, 8 underwent surgical treatment and in 1 patient, lesion was diagnosed on transbronchial biopsy and effectively treated with corticosteroid. Two cases were associated with chronic sclerosing sialadenitis or lymphadenopathy, in which many IgG4-positive plasma cells were also identified by immunostaining. The clinicopathologic similarities between IPT of the lung and sclerosing pancreatitis suggest that IgG4-related immunopathologic processes might be involved in the pathogenesis of the pulmonary lesions.

Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of Th1- and Th2-type pulmonary granuloma fibroblasts.

Interleukin-13 (IL-13) has emerged as a major cytokine mediator of fibroblast activation and pulmonary fibrosis. Normal (from noninflamed lung), Th1-type (induced by the pulmonary embolization of purified peptide derivative-coated beads in mice sensitized to purified peptide derivative), and Th2-type (induced by the pulmonary embolization of Schistosoma mansoni egg antigen-coated beads in mice sensitized with S. mansoni eggs) primary fibroblast cell lines all exhibited constitutive gene expression of two receptor chains that bind and signal IL-13-mediated cellular events: IL-4Ralpha and IL-13Ralpha1. However, all three fibroblast cell lines exhibited divergent synthetic and proliferative responses to the exogenous addition of either recombinant IL-13 or a chimeric protein comprised of IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), which targets and kills IL-13 receptor overexpressing cells. The exogenous addition of IL-13 to Th1-type and Th2-type fibroblast cultures significantly increased the cellular expression of IL-13Ralpha2, which may function as an IL-13 decoy receptor. After a 24-hour exposure to IL-13, the total collagen generation and cellular proliferation by Th2-type fibroblasts were significantly higher than that observed in similar numbers of normal and Th1-type fibroblasts. In addition IL13-PE, which binds with highest affinity to IL-13Ralpha2, exhibited down-regulatory effects on proliferation and matrix generation expression by Th1- and Th2-type, but not normal, fibroblasts. Thus, these data demonstrate that fibroblasts derived from murine pulmonary granulomas exhibit divergent expression of functional IL-13 receptor and this expression dictates the responsiveness and susceptibility to recombinant IL-13 and IL-13 immunotoxin, respectively.

Defective in vivo induction of functional type 2 cytokine responses in aged mice.

Aged mice have various defects in their immune system. We report that following in vivo challenge with type 2 cytokine-inducing Schistosoma mansoni eggs, aged mice fail to produce type 2 cytokines and also have impaired antigen-specific antibody production. Using two separate type 2 cytokine-dependent in vivo models, the synchronous pulmonary schistosome egg granuloma model and infection with the gastro-intestinal nematode Nippostrongylus brasiliensis, aged mice were shown to have a dramatically impaired capacity to elicit a functional type 2 response, i. e. respectively, impaired pulmonary granulomas and delayed rejection of intestinal worms. Aged mice did not develop eosinophilia and had impaired production of antigen specific IgE. Defective induction of type 2 responses was associated with negligible IL-2 and elevated IFN-gamma production by cells from aged mice. Naive aged mice had increased numbers of Th1, Th2 and Tc1 cells compared to young animals. In vivo type 2 challenge increased the frequencies of Th1 and Tc1 cells and reducing Th2 cell numbers in aged mice. These data demonstrate that a consequence of ageing is a profound in vivo defect in the capacity to elicit type 2 cytokine responses and such an impairment in type 2 responsiveness may account for the increased incidence of various type 1 cytokine-mediated diseases in aged individuals.

In vivo regulation of macrophage IL-12 production during type 1 and type 2 cytokine-mediated granuloma formation.

IL-12 is a pivitol cytokine that promotes NK cell activity and Th1 (type 1)-mediated immune responses. This study analyzed the cytokines that regulate macrophage (M phi) IL-12 production in vitro and in vivo. IL-12 was produced by elicited but not resident peritoneal M phi stimulated with endotoxin. Addition of graded doses of cytokines (0.1 to 10 ng/ml) indicated that the Th1-related (type 1) cytokine, IFN-gamma, augmented endotoxin-stimulated IL-12 production by nearly sixfold in oil-elicited M phi. TNF-alpha also increased production but only at the 10 ng/ml concentration. In contrast, the Th2-related (type 2) cytokines, IL-4 and especially IL-10, were profoundly inhibitory. IL-1 beta and IL-2 had no effect. For in vivo analysis, type 1 and type 2 cytokine-mediated lung granulomas (GR) were induced in presensitized mice by embolization of beads coupled to purified protein derivative of Mycobacteria tuberculosis or soluble Ags derived from Schistosoma mansoni eggs. Analysis of M phi isolated from type 1, type 2, or control pulmonary GR revealed that M phi of type 2 GR develop impaired IL-12-producing capacity. Depletion studies using anti-IFN, anti-IL-12, anti-IL-10, and anti-IL-4 neutralizing polyclonal Abs corroborated the in vitro studies. Anti-IFN or anti-IL-12 reduced IL-12 production by M phi from type 1 GR (70 to 80%) as well as IFN and IL-12 production by draining lymph nodes (75 to 90%). Conversely, anti-IL-10 and anti-IL-4 reversed the impaired IL-12 production observed in type 2 GR M phi. These data indicate a positive feedback stimulation of IL-12 production by IFN that is regulated by IL-10 and IL-4 in vivo.

Interleukin-6 and interleukin-1 beta production in a pediatric plasma cell granuloma of the lung.

Plasma cell granuloma (PCG) is a pseudotumor of unknown origin. It is frequently accompanied by acute-phase clinical and biological signs that resume after complete surgical removal, suggesting production of soluble mediators. We therefore investigated the role of cytokines in a previously healthy 10-year-old boy with a PCG of the lung and systemic symptoms. In this case, very high serum levels of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) were found before tumor excision, associated with inflammatory signs including major hyper-gamma-globulinemia. Pathologic analysis of the tumor showed an accumulation of fibroblasts and plasma cells producing immunoglobulins. Local production of IL-1 beta and IL-6 could be demonstrated at the messenger RNA (mRNA) level by the reverse transcriptase polymerase chain reaction and could be attributed to inflammatory cells by in situ hybridization and immunohistochemistry, whereas plasma cells exhibited membrane expression of the IL-6 receptor. Postsurgery follow-up showed rapid normalization of serum IL-1 beta and IL-6, whereas inflammatory protein levels decreased. This confirms the local production of cytokine within the PCG and raises the question of whether a dysregulation of cytokine production initiates the disease.

Seven patients with plasma cell granuloma (inflammatory pseudotumor) of the lung, including two with intrabronchial growth: an immunohistochemical and electron microscopic study.

Seven patients (mean age, 50.7 +/- 20.4 years; range 21-77) with plasma cell granuloma (PCG) of the lung are reported. Cough and sputum were the most common presenting symptoms, followed by fever. Elevated erythrocyte sedimentation rate and serum C-reactive protein levels were found in all patients tested. Radiologically, five cases presented as solitary, well-circumscribed masses and two as ill-defined, pneumonia-like densities. One showed focal calcification. No predilection of occurrence was observed in either lobe of the lung. Histologically, the lesions consisted of a proliferation of mature plasma cells and reticulo-endothelial cells supported by a stroma of granulation tissue, with varying degrees of myxoid change or collagenization. Angioinvasion within the lesion was observed in 4 of the 7 cases. Immunohistochemical staining revealed the IgG-predominant polyclonal nature of the plasma cells, indicating a reactive inflammatory process rather than a neoplastic one. Electron microscopy confirmed the benign nature of the plasma cells with fibroblast and myofibroblast proliferation admixed with that of other inflammatory cells.

Corticosteroids in the management of unresected plasma cell granuloma (inflammatory pseudotumor) of the lung.

The case of a 10-year-old girl with plasma cell granuloma of the lung and an associated hypergammaglobulinemia is reported. A thoracotomy and biopsy were done. Total resection would have required a pneumonectomy. She was treated with an immunosuppressive course of prednisone, which resulted in a reversal of the infiltrative process and the hypergammaglobulinemia.