Lethal Midline Granuloma Research Articles

Polymorphic reticulosis is a neoplasm of large granular lymphocytes with CD3+ phenotype.

Polymorphic reticulosis, a type of lethal midline granuloma (LMG), has been referred to as nasal T-cell lymphoma (NTL) because of its proliferating cells' positive reactivity to anti-T-lymphocyte antibodies. Recently, several studies have suggested that proliferating cells in NTL may be natural killer (NK) in nature. NK cells and human nonmajor histocompatibility-restricted cytotoxic T-lymphocytes have the morphology of large granular lymphocytes (LGL) (i.e., a high cytoplasmic:nuclear ratio and cytoplasmic granules). Whether NTL-LMG possesses an LGL morphology is examined in this study. Two lymph node smears, peripheral blood showing a leukemic picture, and an electron microscope (EM) examination of a cutaneous lesion, respectively, were obtained from four patients with NTL-LMG. Immunohistochemical examination of the proliferating cells and of the Epstein-Barr virus (EBV) genome by both polymerase chain reaction and in situ hybridization also were performed. All patients presented with necrotic and granulomatous lesions in the upper respiratory tract. Histology showed polymorphous cellular infiltrates containing large atypical cells with positive reaction to CD3 (three patients), CD43 (two patients), CD45RO (two patients), and OPD4 (one patient). Imprint smears revealed azurophilic large membrane-delimited granules in an ample cytoplasm, which was confirmed by EM. The presence of the EBV genome in the tumor cells was observed in one patient. The current findings showed that NTL-LMG or polymorphic reticulosis is a proliferation of LGL with a CD3+ phenotype.

Lethal Midline Granuloma; Diagnosis and Treatment

Lethal Midline Granuloma; Diagnosis and Treatment

Epstein-Barr virus (EBV) in extranodal T-cell non-Hodgkin's lymphomas (T-NHL). Identification of nasal T-NHL as a distinct clinicopathological entity associated with EBV.

T-cell Non-Hodgkin's lymphomas (T-NHL) can be defined as clonal malignant proliferations related phenotypically and functionally to normal T-cell populations of the lymphoid tissue. There is increasing evidence that T-NHL with similar morphology but originating from different sites differ in their clinical behaviour, immunophenotypic features, oncogene expression and relation with oncogenic viruses such as HTLV-I and EBV. Indeed, it has been shown that the prevalence of EBV in T-NHL is related to the site of origin. Thus, EBV was found in nearly all nasal T-NHL but only in a proportion of primary nodal, lung, gastrointestinal and Waldeyer's ring T-NHL while it was undetectable in most primary cutaneous T-NHL. Besides their constant association with EBV, nasal T-NHL display peculiar clinical, histological, immunophenotypic and genotypic features. They present clinically as lethal midline granuloma and histologically as pleomorphic malignant tumours variably associated with angiocentricity, angioinvasion and necrosis. Moreover, they frequently exhibit extensive loss of T-cell antigens, including CD3 and TCR alpha beta and gamma delta proteins, usually express the Natural Killer (NK)-related CD56 antigen and frequently show absence of clonal rearrangements of TCR beta, gamma and delta loci. Therefore, among T-NHL, nasal T-NHL can be regarded as a distinct clinicopathologic entity associated with EBV, which could be derived either from immature T-cells or from NK cells.

Sinonasal lymphomas.

Advances in immunocytochemical phenotyping and molecular genetics have nearly resolved the histopathologic and therapeutic quandaries brought about by a diagnostic nomenclature that provided little guidance in the management of midfacial necrotizing lesions. Gone are terms like midline granuloma syndrome, lethal midline granuloma, polymorphic reticulosis, lymphomatoid granulomatosis, midline destructive granuloma, and idiopathic midline destructive disease. They have been replaced by the appreciation that the majority of the lesions are lymphomas of the sinonasal tract. The lymphomas are of B- or T-cell lineage and have a broad biologic spectrum from low to high grade. Still to be addressed are apparent geographic differences in biologic behavior, the epidemiologic significance of a preponderance of T-cell nasal lymphomas in the Orient, and optimum therapeutic regimens.

Angiocentric lymphoma

Angiocentric T-cell lymphoma is a rare type of extranodal lymphoma that has, in the past, been dispersed amongst a variety of eponymous ‘pseudolymphomatous’ disorders. In this article the relationship of angiocentric T-cell lymphoma to the older descriptions of so-called lymphomatoid granulomatosis, Stewart's lethal midline granuloma and histiocytic cytophagic panniculitis is discussed. The characteristic histological, immunophenotypic, genotypic and clinical features are described.

Epstein-barr virus in patients with polymorphic reticulosis (lethal midline granuloma) from china and japan

Polymorphic reticulosis is one of several diseases constituting lethal midline granuloma (LMG). Previous immunohistochemical studies suggested a T-cell nature of proliferating cells; the term nasal T-cell lymphoma (NTL-LMG) has since been used widely. The authors' previous study in Asian countries showed the clustering of Mongolian patients with NTL-LMG, but the frequency varied with geographic area; it was much higher in Korea and southwest Japan (Okinawa) than in Shanghai and Honshu, Japan. Recently an etiologic role of Epstein-Barr virus (EBV) for the development of NTL-LMG has been postulated. In this study, the presence of EBV and human T-cell lymphocytic leukemia virus type 1 (HTLV-1) genomes were examined in NTL-LMG patients from Southwest Japan (Okinawa, 10 patients), another Japanese district (Honshu, 21 patients), and Shanghai, China (5 patients). All of the tissues from different geographic sites were analyzed at one central location. Immunohistochemistry showed that proliferating large cells were positive for CD43 and/or CD45RO, identical with reported NTL-LMG cases. Polymerase chain reaction (PCR) revealed the presence of EBV genome in the NTL-LMG lesions, but the frequency varied according to the geographic area: 67% in Okinawa, 33% in Honshu, and 100% in Shanghai. In situ hybridization provided positive signals in the nuclei of proliferating cells. Expression of latent membrane protein in the proliferating cells of cases positive for EBV by PCR and in situ hybridization was confirmed. The results suggest that the EBV may play a role in the development of NTL-LMG. However, the variation of frequency of EBV genome in different geographic locations suggests that EBV infection may not be an indispensable condition for the disease.

Lethal midline granuloma in Okinawa with special emphasis on polymorphic reticulosis.

Lethal midline granuloma (LMG) is a clinical term used to describe a condition which may be manifested histologically as Wegener's granulomatosis (WG), polymorphic reticulosis (PR), and malignant lymphoma (ML). WG is an inflammatory disease, and PR and ML are considered to represent a neoplastic proliferation of lymphoreticular cells. In this report, twenty‐two cases of LMG in Okinawa were examined. The frequency of LMG per 100,000 outpatients of the ear, nose and throat clinic in Okinawa was 67, and the higher frequency of PR (27) and ML (34) in Okinawa than in other districts of Japan was characteristic. Polymerase chain reaction, in situ hybridization, and immunohistochemical studies showed that the proliferating cells in PR were CD43+ and simultaneously contained Epstein‐Barr viral genome in their nuclei. The higher frequency of PR and ML in Okinawa is discussed in conjunction with a review of pertinent literature: multiple factors including genetic, viral environmental, and socioeconomic factors seem to affect the frequencies of these diseases.

Clonality, expression and methylation patterns of the Epstein-Barr virus genomes in lethal midline granulomas classified as peripheral angiocentric T cell lymphomas.

We analysed the terminal repeats of Epstein-Barr virus (EBV) in DNAs isolated from six lethal midline granuloma (LMG) biopsies. A single fused terminal fragment could be detected in each case, indicating that these angiocentric peripheral T cell lymphomas represent clonal proliferations of cells infected with EBV on a single occasion. Using reverse transcriptase-PCR, we detected EBV nuclear antigen (EBNA) 1 and latent membrane protein (LMP) 1, but not EBNA 2 messages in LMG biopsy RNAs. The splicing pattern of the EBNA 1 message was consistent with the usage of a promoter localized in the BamHI F fragment (F promoter). The BamHI W fragment repeats and LMP-coding sequences were highly methylated in all cases. In contrast, the LMP regulatory sequences were found to be hypomethylated or partially methylated, as in LMP-expressing nasopharyngeal carcinomas.

Epstein-Barr virus subtype distribution in angioimmunoblastic lymphadenopathy.

The tissues of 16 patients bearing a T-cell lymphoma of angioimmunoblastic lymphadenopathy type (AILD-TCL) were investigated for the distribution of Epstein-Barr virus (EBV) subtypes 1 and 2. EBV-association had been proven in these cases by polymerase chain reaction (PCR) for EBV-DNA, in situ hybridization (ISH) for EBV-encoded small nuclear RNAs (EBER) and immunohistology for EBV-encoded latent membrane protein (LMP). PCR and EBER-ISH produced mostly identical results, but some cases were positive with only one of the 2 methods employed. LMP was detected in a few large cells of 8/13 cases. Twelve cases were investigated for the distribution of EBV subtypes. One case contained EBV genome of subtype 2, 3 cases contained subtype 1 and 4 cases contained both subtypes. Four cases could not be typed. These findings suggest that in AILD, as in AIDS-associated lymphomas and lymphomas of the lethal midline granuloma type, subtype 2 of EBV may occur, perhaps in relation to an immunodysfunction developing progressively in these patients.

Association of the subtype 2 of the Epstein-Barr virus with T-cell non- Hodgkin's lymphoma of the midline granuloma type [see comments

Lethal midline granuloma (LMG) is associated with Epstein-Barr virus (EBV). The latter has at least two subtypes with different biological properties. The subtypes can be identified by their genomic configuration. Using EBV-RNA (EBER) in situ hybridization and EBV polymerase chain reaction (PCR), we have looked for the presence of EBV in six LMGs and six non-Hodgkin's lymphomas (NHLs) located in the nasopharyngeal region, and determined the subtype of EBV. Six of six LMGs were positive by PCR and EBER in situ hybridization, whereas NHLs were either negative or, in three of six cases, showed few EBER- positive cells considered to be nonneoplastic lymphocytes. The subtype 2 was found in LMG lesions of three of six patients; the remaining three of six patients with LMG had the generally occurring subtype 1. The results indicate that the association of EBV with NHL may depend more on tumor type than on its localization. The occurrence of the rare subtype 2 in LMG may relate to a covert immune defect.

Association of the Subtype 2 of the Epstein-Barr Virus With T-Cell Non-Hodgkin's Lymphoma of the Midline Granuloma Type

Lethal midline granuloma (LMG) is associated with Epstein-Barr virus (EBV). The latter has at least two subtypes with different biological properties. The subtypes can be identified by their genomic configuration. Using EBV-RNA (EBER) in situ hybridization and EBV polymerase chain reaction (PCR), we have looked for the presence of EBV in six LMGs and six non-Hodgkin's lymphomas (NHLs) located in the nasopharyngeal region, and determined the subtype of EBV. Six of six LMGs were positive by PCR and EBER in situ hybridization, whereas NHLs were either negative or, in three of six cases, showed few EBER-positive cells considered to be nonneoplastic lymphocytes. The subtype 2 was found in LMG lesions of three of six patients; the remaining three of six patients with LMG had the generally occurring subtype 1. The results indicate that the association of EBV with NHL may depend more on tumor type than on its localization. The occurrence of the rare subtype 2 in LMG may relate to a covert immune defect.

Lymphomas of the head and neck. 1: Nasofacial T-cell lymphoma.

Nasofacial T-cell lymphoma includes diseases otherwise called "lethal midline granuloma" and "necrosis with atypical cells". It is characterised by relentless destruction of nose and palate in particular but the lymphoma remains localised to the head and neck. The age of onset ranges from 10 to 87 and the survival ranges from a few months to several years. The histological appearances are of a polymorphic infiltrate but including atypical T cells in a background of macrophages. There is a strong association with Epstein-Barr virus infection.

Cases of lethal midline granuloma (polymorphic reticulosis) at our department in a recent 10-year period

We had 18 patients (15 males and 3 females) with lethal midline granuloma (polymorphic reticulosis) in the period from 1981 to 1990. This number was about 5.6% of the total number of patients with malignant head and neck tumors that we encountered during this period. An average of 9.1 months separated the first appearance of disease and the beginning of treatment. Most of the 18 patients underwent both radiation therapy and chemotherapy (COP, CHOP, MACOP-B), but, since their disease had reached an advanced stage, 3 underwent radiation therapy only, 3 underwent chemotherapy only, and 1 received no radical therapy at all. Of the 18 patients, 13 died of the disease. In of 6 of these, the disease was confined to the local lesion. The 5-year cumulative survival rate was 15.7% (Kaplan-Meier). Fourteen autopsy studies revealed that tumor cells had invaded the liver (92.8%), lung (92.8%) and spleen (71.4%) and in all cases it was in leukemic patterns. Fifteen cases were studied for tumor surface marker phenotype, but none was found to be positive for L26, CD43, Leu M1 (CD15), or MAC 387. Five cases were positive for UCHL-1 (CD45RO) and 10 cases were positive for lysozyme. All cases were positive for Ki-1 (CD30).

Lethal midline granuloma: impact of imaging studies on the investigation and management of destructive mid facial disease in 13 patients.

In 13 patients presenting as lethal midline granuloma (LMG), computed tomography proved essential for determining the extent of the disease, guiding biopsy and planning radiotherapy. Magnetic resonance imaging (MRI) was also helpful for the latter, because it could distinguish fluid retained within the paranasal sinuses from solid masses and tumour from granulation tissue; it was of little value for detecting bone lysis. Eight of the 13 patients proved to have T-cell lymphoma, two had Crohn's disease, in one the lesion was factitious and two had granulomas without diagnostic histological features.

Clinicopathological spectrum of Epstein-Barr virus-associated T cell malignancies.

It has been recently demonstrated that the Epstein-Barr virus (EBV) can infect human thymocytes and may be involved in the T cell neoplasms, in addition to African Burkitt's lymphoma, nasopharyngeal carcinoma and Hodgkin's disease. Four distinct clinicopathologic categories of EBV-associated T cell malignancies have been recognized. The angiocentric T cell lymphoma or lymphomatoid granulomatosis involving the nose (or midline lethal granuloma) and skin is frequently EBV-associated. The other 3 groups include angioimmunoblastic lymphadenopathy-like lymphoma, node-based T immunoblastic lymphoma which may contain Reed-Sternberg-like giant cells (Hodgkin's-like lymphoma), and T cell lymphoma resembling malignant histiocytosis. Both the CD4 and CD8 T cell subsets, and a hitherto undefined T lineage lacking CD4/CD8 expression have been involved. The common clinical features are prolonged fever, skin lesions, lymphadenopathy, hepatosplenomegaly, and pancytopenia. Serologic assays suggest that a chronic active EBV infection may exist in most of these patients. The EBV genomes appear to proliferate in clonal and episomal form in the neoplastic cells which show expression of latent membrane proteins. Although an indolent local phase may exist, the clinical course is aggressive for most patients with frequent development of drug resistance to conventional chemotherapy. EBV-associated T cell lymphoma constitutes a separate entity of virus-associated human diseases and opens a potential field to investigate the pathogenesis of EBV-associated human malignancies.

Non-Hodgkin's lymphoma confined to the nasal cavity: Its relationship to the polymorphic reticulosis and results of radiation therapy

From 1975 through 1988, nine patients with locally confined nasal non-Hodgkin's lymphoma (NHL) were treated with radiation therapy in the Department of Radiology, Chiba University Hospital. Immunohistochemical study disclosed that all NHL's have T-lineage. Additionally, unique histological pictures of polymorphism, angiodestruction, and necrosis were seen in most of cases. These three findings are the histological features of polymorphic reticulosis (PMR), which is the main cause of lethal midline granuloma and has recently been shown to belong to T-cell malignancy. Therefore, it is concluded that the nasal T-cell NHL and PMR are really a single disease entity. The predominance of the T-cell lymphoma in the nasal cavity as well as its histological distinctness clearly indicate that the head and neck extranodal NHL cannot be discussed together. Although the disorder was considered to be locally limited at presentation, only 3 of the 9 patients with nasal NHL could be induced into long-term remission with involved field radiotherapy. The distant extranodal spread was the primary cause of failure. Multimodality treatment using intensive chemotherapy might improve the prognosis of nasal NHL.

Letter to the editor: Epstein-barr virus and T-cell lymphoma

American Journal of HematologyVolume 36, Issue 2 p. 160-160 Letter to the EditorFree Access Letter to the editor: Epstein-barr virus and T-cell lymphoma Raymond Liang, Raymond Liang Department of Medicine University of Hong Kong Queen Mary Hospital, Hong KongSearch for more papers by this authorDarryl Shibata, Darryl Shibata Department of Pathology University of Southern California School of Medicine, Los AngelesSearch for more papers by this author Raymond Liang, Raymond Liang Department of Medicine University of Hong Kong Queen Mary Hospital, Hong KongSearch for more papers by this authorDarryl Shibata, Darryl Shibata Department of Pathology University of Southern California School of Medicine, Los AngelesSearch for more papers by this author First published: February 1991 https://doi.org/10.1002/ajh.2830360220Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Anagnostopoulos L, Herbst H, Niedobitek, et al.: Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki–I positive anaplastic large cell lymphoma by combined Southern Blot and in situ hybridization. Blood 74: 810– 816, 1989. 2 Jones JF, Shurin S, Abramowsky C, et al. T–cell lymphomas containing Epstein–Barr viral DNA in patients with chronic Epstein–Barr virus infections. N Engl J Med 318: 733– 741, 1988. 3 Weiss LM, Movahed LA, Warnke RA, et al. Detection of Epstein–Barr viral genomes in Reed–Sternberg cells of Hodgkin's disease. N Engl J Med 320: 502– 506, 1989. 4 Harabuchi Y, Yamanaka N, Kataura A, et al. Epstein–Barr virus in nasal T–cell lymphomas in patients with lethal midline granuloma. Lancet i: 128– 130, 1990. 5 Baer R, Bankier AT, Baggin MD, et al. DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature 310: 207– 211, 1984. Citing Literature Volume36, Issue2February 1991Pages 160-160 ReferencesRelatedInformation

いわゆる進行性鼻壊しょの症例

A 54-year-old man was referred to the Self-Defense Forces Central Hospital for evaluation of nasal obstruction, a nonhealing ulcer of the hard palate, severe headache and spiking fever. A necrotic and hemorrhagic tumor was found in the nasal cavity. The original biopsy revealed a dense cellular infiltrate to the submucosa in which mononuclear cells predominated. Chest roentgengram, ECG, clinical examination, serology and urinalysis were all within normal limits. The diagnosis was lethal midline granuloma. Radiotherepy was administered in a dose of 5000 rads to the involved areas, and predonisolone, cyclophosphamide, 6-MP and vinclistine were given. The treatment was effective, localized lesion was controlled, and the necrosis disappeared. Two months later, painful soft tissue swellings appeared in his thigh, scapula and hip. A biopsy of the hip lesion showed atypical mononuclear cells infiltrating the subcutaneous area and muscle layers. Serum CPK rose markedly and rapidly. Three weeks later the patient died of respiratory failure. This lethal midline granuloma was a systemic and progressive type, and the nasal involvement was the first manifestation of the disease.

Computed tomography of lethal midline granuloma

In order to clarify the CT findings of lethal midline granuloma(LMG) diagnosed clinically or histopathologically, the authors retrospectively analyzed 12 patients who were ween at Kyungpook National University Hospital from February 1985 to August 1989. CT showed nasal mucosal thickening and/or soft tissue mass( 9 cases), spreading of the lesions along the facial subcutaneous fat plane(8 cases), invasion into the paranasal sinuses(5 cases), bone destruction(5 cases) nasopharyngeal mass lesion(2 cases), and extension of the lesion into the infratemporal fossa(1 case). In spite of the fact that CT does not make definitive diagnosis of LMG, it permits evaluation of the extent of the lesion, detection of the combined lesion, differential diagnosis, and close monitoring of its evolution under treatment.

Angiocentric immunoproliferative lesion/T-cell non-Hodgkin's lymphoma and the acquired immune deficiency syndrome: A case report and review of the literature

The lesions known as lymphocytic vasculitis, polymorphic reticulosis (midline malignant reticulosis, lethal midline granuloma), lymphomatoid granulomatosis, and angiocentric lymphoma form what have been collectively termed the angiocentric immunoproliferative lesions (AIL). Because of recent reports demonstrating clonal rearrangements of the T-cell receptor in these lesions, the AIL are now thought to represent a continuous spectrum of post-thymic T-cell non-Hodgkin's lymphoma (NHL). NHL associated with the acquired immune deficiency syndrome (AIDS) represents intermediate or high-grade B-cell malignancies in HIV-infected patients that may be etiologically related to the Epstein-Barr virus (EBV). There have been reports of EBV-associated T-cell NHL, AIL, and large granular lymphocyte (LGL) proliferations, as well as HIV-associated T-cell neoplasia, LGL/T-cell proliferations, and AIL. We describe a case of polymorphic reticulosis (lethal midline granuloma) arising in an HIV-infected individual, who later progressed to AIDS, and review the literature on HIV-associated and EBV-associated T-cell neoplasia, LGL/T-cell proliferations, and AIL. The etiology of this AIL/T-cell NHL, especially in relation to EBV and HIV, is discussed.