'Inflammatory myofibroblastic tumour'-like dedifferentiation of anaplastic lymphoma kinase-rearranged lung adenocarcinoma.

AIMS: Anaplastic lymphoma kinase (ALK) functions as an oncogenic driver in a subset of haematopoietic, epithelial and mesenchymal neoplasms. Activation of ALK most commonly occurs through gene fusion events, the presence of which predicts response to ALK-targeted inhibitors in some tumour types. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions represent the majority of ALK rearrangements in lung adenocarcinomas and were, until recently, thought to be exclusive to that tumour type. However, recent work has identified EML4-ALK fusions in ~20% of inflammatory myofibroblastic tumours (IMTs), particularly in those arising in the lung. Here, we present a patient with an ALK-rearranged poorly differentiated lung adenocarcinoma with a predominant sarcomatoid component that was morphologically indistinguishable from IMT. METHODS AND RESULTS: Targeted next-generation sequencing revealed EML4-ALK rearrangements in both components, with identical fusion sequences. Copy number analysis demonstrated focal gain of the MYC gene in the IMT-like component. The findings support a diagnosis of ALK-rearranged lung adenocarcinoma with IMT-like dedifferentiation. CONCLUSIONS: Our findings suggest that ALK-driven epithelial and mesenchymal neoplasms exist on a morphological spectrum, and emphasize the need to consider translocation testing in pulmonary tumours with unusual sarcomatoid morphology.

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.

[Protein and mRNA expression of osteopontin in lung cancer and clinical significance thereof].

OBJECTIVE: To investigate the protein and mRNA expression of osteopontin (OPN) in the lung cancer tissue and explore the roles thereof in the development and progression of lung cancer. METHODS: Immunohistochemistry and in situ hybridization were used to detect the protein and mRNA expression of OPN in 57 specimens of lung cancer tissue, 30 specimens of inflammatory pseudotumors and 20 specimens of pulmonary bulla, all obtained during operation. RESULTS: The OPN protein expression rate of the lung cancer tissue was 57.9% (33/57) , significantly higher than that of the inflammatory pseudotumor (16.7%, 5/30, chi2 = 13.581, P = 0.000). The OPN mRNA expression rate in the lung cancer tissue was 71.9% (41/57), significantly higher than that of the inflammatory pseudotumor (30.0%, 9/30, chi2 = 14. 138, P = 0.000). All the 20 specimens of pulmonary bullae were negative in the expression of OPN, both at the protein and mRNA levels. The OPN protein and mRNA expression rates of the lung cancer tissues with lymph node metastasis were 71.1% (27/38) and 86.8% (33/38) respectively, both significantly higher than those of the lung cancer tissue without lymph node metastasis [31.6% (6/19) and 42.1% (8/19) respectively, chi2 = 6.558, P = 0.010, and chi2 = 10.438, P = 0.001]. The OPN protein and mRNA expression rates of the non-small lung cancer tissues were 68.1% (32/47) and 78.7% (37/47) respectively, both significantly higher than those of the small lung cancer tissues [10% (1/10) and 25% (4/10) respectively, chi2 = 11.412, P = 0.001, and chi2 = 6.124, P = 0.013]. The OPN protein expression was positively correlated with the OPN mRNA expression in the lung cancer tissues (r = 0.623, P = 0.001). The 57 patients with lung cancer after surgery were followed up for 28 (24-40) months, 8 of the 32 patients with both positive OPN protein and mRNA expression had recurrence and 13 patients had a distant metastasis, while only 1 of the 15 cases negative in both OPN protein and mRNA expression showed recurrence (chi2 = 14.258, P = 0.000). 12 patients died in the both positive expression group but no patient died in the both negative expression group (chi2 = 7.554, P = 0.006). CONCLUSION: Over-expressions of OPN protein and OPN mRNA are found in lung cancer tissues and their expressions are correlated to the prognosis and metastasis of lung cancer.

Involvement of 2p23 in pulmonary inflammatory pseudotumors.

Pulmonary inflammatory pseudotumors (IP) are rare mesenchymal proliferations that have a polymorphic histology and an unpredictable biologic behavior. The histologic spectrum of IP has led to uncertainty as to whether this tumor has a reactive or neoplastic pathogenesis. Reports of extrapulmonary IP have identified clonal chromosomal aberrations involving 2p23 in the region of the ALK gene. Using fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 and immunostaining for the ALK gene product, we studied formalin-fixed, paraffin-embedded tissues of pulmonary IP and found a subset (33%) with 2p23 aberrations. We suggest that chromosomal rearrangements and ALK immunostaining may be helpful in the diagnosis of a group of pulmonary IP and should be investigated as a potential tool for predicting their future biologic behavior. An association with anaplastic large-cell lymphoma was also observed. HUM PATHOL 32:428-433.

Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin.

The inflammatory myofibroblastic tumor (IMT) is a distinctive but controversial lesion, usually occurring during childhood, composed of fascicles of bland myofibroblastic cells admixed with a prominent inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. Often affecting the lung and associated with constitutional symptoms, this lesion has been variously termed plasma cell granuloma, inflammatory pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma to reflect divergent views concerning its pathogenesis and level of malignancy. Cytogenetic analysis of an intra-abdominal myxoid hamartoma, a probable variant of this lesion, and a pulmonary IMT demonstrated clonal chromosomal abnormalities, lending support to the view that the IMT might be a neoplasm. There have been few cases studied to date, however, and the extent of cytogenetic anomalies in IMTs is not known. Karyotype analyses were performed on IMTs showing typical histologic features from three children. In addition, one case was studied by fluorescence in situ hybridization. Seventeen of 20 metaphase cells examined from a pulmonary IMT in a 5.5-year-old girl had an abnormal 47,XX+r(ring) karyotype. Fluorescence in situ hybridization studies demonstrated that the ring chromosome contained sequences of chromosome 8. Of 40 metaphase cells studied from a mesenteric IMT in an 8-month-old boy, 12 showed clonal aberrations, characterized as 43,XY,add(1)(p36),add(2)(p24),-6,der(14,22)(q10;q10),-19. Each of 20 metaphase cells examined from a retroperitoneal IMT in a 14-year-old girl contained complex clonal and nonclonal aberrations, characterized as 46-47,X,-X,add(2)(p22),add(2)(q13),+add(2)(q13),+5,-6,+i(7)(p10),add(8)( p11.2),+del(9)(p13),add(11)(p11.2)add(11)(q25),-13,-16,-18,add(19)(q13.1 ),add(19)(q13.1),+20,-21,-22,+mar1,+1-2mars. The presence of clonal chromosomal aberrations in all of the three tumors indicates that the IMT is a neoplastic proliferation.

Clonal changes in inflammatory pseudotumor of the lung: a case report.

BACKGROUND: Pulmonary inflammatory pseudotumor, also known as plasma cell granuloma among many other names, is widely believed to be an inflammatory or reactive lesion rather than a neoplasm, although its pathogenesis is still controversial. METHODS: Cytogenetic analysis was performed on a lung mass that showed typical clinical and pathologic features of inflammatory pseudotumor. Ultrastructural and immunohistochemical studies were performed in addition to routine histologic examination. RESULTS: Cytogenetic study of the lesion revealed clonal anomalies of t(1;2)(q21;p23) and del(4)(q27). The patient, a 30-year-old woman, presented with an asymptomatic but enlarging right lower lobe mass for which partial right lower lobectomy was performed. The lung mass was well circumscribed radiographically and grossly. Microscopically, it was characterized by a loosely arranged spindle cell proliferation with prominent plasma cell infiltration. Fibroblastic and myofibroblastic differentiation of the spindle cells was demonstrated by ultrastructural and immunohistochemical studies. CONCLUSION: To the authors' knowledge, this is the first report of clonal cytogenetic changes in a clinically and pathologically typical case of inflammatory pseudotumor in the lung. This finding suggests that pulmonary inflammatory pseudotumor might be a true neoplasm rather than a purely inflammatory or reactive lesion.