BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial.

BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.

Assessment of diagnostic criteria between primary cutaneous anaplastic large-cell lymphoma and CD30-rich transformed mycosis fungoides; a study of 66 cases.

BACKGROUND: Transformed mycosis fungoides (TMF) large cells may express CD30 antigen, and because of this, the differential diagnosis between CD30-rich TMF and primary cutaneous anaplastic large-cell lymphoma (cALCL) may be difficult, and especially in distinguishing cALCL associated with MF vs. CD30-rich TMF. OBJECTIVES: To find clinical, histological and molecular diagnostic features useful for differential diagnosis between cALCL and CD30-rich TMF. To analyse and compare the prognostic value of clinical and pathological factors in these two diseases. MATERIAL AND METHODS: We conducted a retrospective study (1999-2012) of 32 patients with cALCL and 34 with CD30-rich TMF, seen in reference centres of the French Study Group of Cutaneous Lymphoma. Clinical, histological and molecular features were analysed and compared to determine their diagnostic and prognostic value. RESULTS: Comparison of the two groups showed that age ˃ 60 years, ≥ 5 skin lesions, early progression, absence of spontaneous regression and trunk involvement were significantly associated with the diagnosis of TMF. Abnormal T-cell phenotype and perforin expression were significantly more frequent in cALCL (both P < 0·001). Overall survival (OS) at 5 years was 77·4% for cALCL and 20·7% for CD30-rich TMF. Stage T3, ≥ 5 skin lesions, lower limb involvement for cALCL and stage T4, extracutaneous involvement, B symptoms, high levels of lactate dehydrogenase for CD30-rich TMF were associated with poor OS and progression-free survival. DUSP22 gene rearrangement had no diagnostic or prognostic value. CONCLUSIONS: Clinical features and outcome are the most discriminative to differentiate the two entities. Even histological and molecular markers were not fully specific; abnormal vs. normal T-cell phenotype and perforin expression may constitute helpful tools.

La maladie de Castleman : aspects anatomopathologiques.

Histologically, Castleman's disease associates three subtypes: 1-the vascular hyaline (HV) subtype more often seen in unicentric forms; 2-the plasmacytic (PV) subtype, more frequently associated with the HHV8+ and idiopathic multicentric form; 3-the mixed subtype associating both HV and PV aspects that may be encountered in any type of Castleman's disease. If the diagnosis of unicentric (isolated mass) and multicentric HHV8+ Castleman's disease is easy, the diagnosis of the idiopathic multicentric form remains particularly difficult because it is at the crossroads of many other pathologies (infectious, tumoral and dysimmune), making an anatomoclinical comparison necessary. The role of the pathologist, in the context of disseminated lesions (polyadenopathy and splenomegaly), is to identify lesions that may be part of Castleman's disease, to systematically perform HHV8 testing and to perform complete phenotyping associated with molecular analysis (B and T-cell clonality) in order to rule out a lymphomatous process and certain infectious etilogies. In all cases, its role will be a warning bell and the diagnosis of Castleman's disease will be retained only after a rigorous anatomic and clinical confrontation. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

Diagnostics différentiels de la maladie de Castleman.

Clinicians are sometimes confronted with the diagnostic difficulties of the idiopathic form of Castleman's Disease (iMCD). As this review reports with demonstrative clinical cases, iMCD can mimic various serious systemic pathologies such as certain autoimmune diseases, Still's disease, POEMS syndrome, and malignant lymphoproliferations, sharing a very similar histology and identical symptoms. To make a diagnosis of iMCD, the clinician must eliminate all the pathologies mentioned above, but he must first think of it and evoke this diagnosis of rare disease before the first symptoms but also know how to evoke this diagnosis again even after several years of evolution of a disease like those mentioned above whose evolution is not favorable. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

[HHV-8 Related immunological and hematological diseases]. / Maladies immunologiques et hématologiques liées à HHV-8.

HHV-8 is an oncogenic Gammaherpesvirinae discovered in 1994 during the HIV pandemic. It is the causative agent of Kaposi's sarcoma, and is also associated with the occurrence of several aggressive B lymphoproliferative disorders. Most of them occur in an immunosuppression setting, usually due to HIV infection. Multicentric HHV8-associated Castleman's disease and KSHV Inflammatory Cytokine Syndrome (KICS) are primarily reactive entities with prominent systemic features. They illustrate the cytokinic storm induced by HHV-8 in its cell host. On the other hand, HHV-8 can drive proliferation and lymphomagenesis of its plasmablastic cell host, and is associated with a risk to develop aggressive lymphomas with plasmacytic differenciation. Primary effusion lymphoma usually localizes in body cavities and may affect other extra-nodal sites ; its prognostic is poor. Diffuse large B-cell lymphoma HHV-8, NOS affect more commonly nodes and blood and evolve from infected cell of HHV-8 associated Castleman disease. On the contrary, germinotropic lymphoproliferative disorders presents mainly as localized adenopathy with indolent course, and show polyclonality. Histology plays a key role in distinguishing these different entities and need expert reviewing, especially since they may be associated with each other. Besides lymphoproliferative disorders, HHV8 is associated with various hematological manifestations. The aim of this review is to provide an update on the presentation, diagnosis, and management of immunologic and hematologic complications associated with HHV-8.

[Peripheral T cell lymphomas: diagnosis and treatment]. / Lymphomes T périphériques : diagnostic et prise en charge.

Peripheral T cell lymphomas are rare malignancies with aggressive course, with several different subtype described in the 2016 WHO classification. Their distribution across the world is heterogenous, with marked difference between Western and Asian country. Their clinical presentation often comprise extra-nodal involvement, B symptoms and immune system disorder which can lead to wrong diagnosis orientation. Make a right diagnosis need a experienced pathologist in close collaboration with clinical datas. Peripheral T cell lymphomas are in general associated with poor prognosis when treated with anthracyclines-based regimen, and several studies and trials focused on the use of intensified regimen or novel targeted agents, whose proper indication still remain to be clarified.

Splitting bone marrow trephines into frozen and fixed fragments allows parallel histological and molecular detection of B cell malignant infiltrates.

Clonality analysis of the immunoglobulin heavy chain (IgH) gene is helpful in identifying malignant B cell infiltrates in the bone marrow and is usually carried out on separate aspirates or on the same formalin-fixed decalcified bone marrow specimen. To determine whether the removal of the decalcification step would improve the molecular analysis, we first studied 12 bone marrow specimens with lymphoma infiltration split into a fixed and a small frozen fragment. Both the detection rate of IgH gene monoclonality and DNA quality were found to be superior in the frozen part than in the fixed part. Conversely, to evaluate whether the split would compromise histological analysis, we selected a series of 134 bone marrow specimens obtained from patients with small B cell lymphoma and showing IgH monoclonality on the frozen part. The histological detection rate of infiltrated or suspicious infiltrates (95%) on the fixed part was not altered by saving a frozen part.

[Exophtalmia revealing a mantle cell lymphoma]. / Exophtalmie révélant un lymphome du manteau: à propos d'un cas.

INTRODUCTION: Mantle cell lymphoma reached rarely ophtalmic sphere and salivary glands. CAS REPORT: We reported a dry syndrome seen in a 67 year-old patient. The first patological analysis of accessory salivary glands evoked a primary Gougerot-Sjögren syndrome. Secondary, he presented a mantle cell lymphoma. DISCUSSION: The pathological lack of specifity and the discovery of atypical Gougerot-Sjögren syndrome must encourage complementary immunohistochemical study of salivary glands biopsy.

Identification of novel trkA variants with deletions in leucine-rich motifs of the extracellular domain.

The peripheral expression of trkA encoding for NGF receptor was investigated by RNase protection assay. A thymus-specific protected fragment was identified. Using 5' rapid amplification of cDNA ends, three different trkA fragments were characterized. The longer fragment corresponded to the classical trkA L3 transcripts while the two shorter fragments lacked sequences encoding for leucine-rich motifs of the extracellular domain of TrkA, similarly to the trkB L1 and L0 variants. RT-PCR analysis of adult rat tissues showed the expression of trkA L1 transcripts in the thymus, testis, lung and kidney but not in the central nervous system. Their combined expression with trkA L3 transcripts suggests that specific peripheral TrkA oligomers may modulate NGF binding and function in non-neuronal cells.

Distribution of NGF receptors in normal and pathologic human lymphoid tissues.

To identify nerve growth factor (NGF) target cells in normal and pathologic human lymphoid tissues, we have studied the expression of the low-affinity NGF receptor (p75LNGFR) and the high-affinity tropomyosin-related kinase NGF receptor (TrkA). A RNAse protection assay revealed the expression of trk transcripts in thymus, spleen, palatine tonsils and lymph nodes. TrkA immunoreactivity was shown in thymic epithelial cells, cryptic tonsillar epithelium and several monocyte-derived cells including epithelioid and multinucleated Langhans' cells, follicular dendritic cells and interdigitated reticular cells. TrkA immunoreactivity was rarely observed in normal T- and B-lymphocytes, but was intense in lymphoma cells of several B-cell lymphoma subtypes, anaplastic large cell lymphomas and Reed-Sternberg cells. Western blot analysis revealed the presence of p75LNGFR and of p80Trk and glycosylated Trk isoforms (gp110, gp140). p75LNGFR immunoreactivity was detected in epithelial Hassal's bodies, follicular dendritic cells, interdigitated reticular cells, periarteriolar macrophages, endothelial sinusal cells and nerve endings. The broad expression of NGF receptors may be an indicator of neurotrophin activity in lymphoid tissues and suggests their implication in inflammatory or lymphoproliferative disorders.

Expression of NGF receptors in normal and pathological human thymus.

The expression of NGF receptors was investigated in normal human thymus and in thymic hyperplasias, thymomas and thymic carcinomas. By RT-PCR, we detected TrkAI transcripts encoding for the high-affinity NGF receptor. Western blot analysis showed the presence of both TrkA and p75NGFR proteins. In normal thymuses, epithelial subcapsular and medullar cells were TrkA immunoreactive. Interdigitated medullar cells were stained for both TrkA and p75NGFR. While epithelial cells of normal thymuses or benign thymomas exhibited a TrkA positive-p75NGFR negative phenotype, a switch to a TrkA negative-p75NGFR positive phenotype was observed in malignant epithelial cell tumours and was associated with cell proliferation-associated MIB1 expression. Our results argue for a local role of NGF and its receptors on thymic stromal cells both in normal and neoplastic conditions.

Endarteritis and false aneurysm complicating aortic coarctation.

We report a tricky case of endocarditis because of the localization, aortic coarctation, and the pathogenic bacteria Actinobacillus actinomycetemcomitans. Furthermore, we underline the leading role of transesophageal echocardiography in the diagnosis of aortic endarteritis. First, aortitis was treated with antibiotics and, second, successfully operated on.

Intrasinusoidal bone marrow infiltration revealing intravascular lymphomatosis.

Intravascular lymphoma is a rare, often fatal disease characterized by a widespread intravascular proliferation of neoplastic lymphoid cells. Dermatological and bizarre neurological manifestations usually predominate. We report a case of intravascular lymphomatosis with an exceptional clinical presentation showing splenomegaly combined with early bone marrow involvement. The diagnosis was made on bone marrow biopsy examination using both immunohistochemistry and molecular biology analysis. We stress the histopathological features of bone marrow involvement by intravascular lymphoma which allow the prompt recognition of this disease. Early systemic chemotherapy, which represents the only chance of remission in such an aggressive disease, can then be initiated.

Differential expression of NGF receptors in human thymic epithelial tumors.

NGF receptor (TrkA and p75NGFR) expression was investigated in human thymuses, including normal thymuses, thymic hyperplasias, thymomas and thymic carcinomas. TrkAI but not TrkAII transcripts were demonstrated by RT-PCR. In normal thymuses, immunohistochemistry revealed a restricted TrkA-immunoreactivity to epithelial and interdigitated reticular cells, while only interdigitaded reticular cells were immunoreactive for p75NGFR. Thymocytes were negative for both receptors. A switch from the normal TrkA positive-p75NGFR negative phenotype to a TrkA negative-p75NGFR positive phenotype was found in histologically aggressive epithelial cell tumors, suggesting that NGF and its receptors are potentially involved in thymus stroma organogenesis and proliferation.

A possible association between Chlamydiae psittacci infection and temporal arteritis.

Some arguments are in favor of the role of Chlamydia in the pathogenesis of atherosclerosis and some vasculitis. Illustrating this possible relation, we report the case of a patient developing consecutively a Chlamydia psittacci infection and a temporal arteritis. A 73-year-old woman, with no significant medical history, was hospitalized for constitutional symptoms. Three weeks before, she had described fever and sore throat of two days' duration. Since that time, she had remained exhausted and developed a mild intermittent claudication of the jaws. Clinical examination was poor. A biological inflammatory syndrome was noticed. Chest X-ray revealed bilateral interstitial opacities. The titer of anti-C. psittaci antibodies was significant (positive 1g G at 1/2048). Soon after initiation of doxycycline, a temporal arteritis biopsy was performed, due to the persistence of clinical symptoms and high inflammatory syndrome, conclusive for the diagnosis of temporal arteritis. Corticotherapy was added to antibiotic therapy, resulting in the decrease of inflammatory syndrome and an improvement in the general status of the patient. X-ray opacities decreased in three weeks. Serological control after three months showed a decrease of the titer of anti-C. psittacci antibodies to 1/256, confirming the initial diagnosis of Chlamydia pneumopathy. Our observation could provide one more argument for the role of bacteria-like Chlamydia in the pathogenesis of vascular diseases. Prospective seroepidemiological and molecular biology studies could allow us to clarify the association between Chlamydia infections and inflammatory vasculitis-like temporal arteritis.

[Non-penetrating vascular staples prevent myo-intimal hyperplasia and maintain arterial vasomotor reaction]. / Les clips de suture vasculaire non pénétrants limitent l'hyperplasie myo-intimale et maintiennent les réactions artérielles.

OBJECTIVES: Vascular anastomosis is still associated with a significant rate of early or delayed complications, particularly restenosis. We have previously demonstrated that non-penetrating clips can help prevent intimal hyperplasia. The aim of this study was to evaluate how well the use of mechanical clips prevents intimal hyperplasia while maintaining arterial vasomotor function. MATERIAL AND METHODS: An aortic suture was performed in 38 rabbits. A standard closure was used for 15 sutures and a small vascular closure staple (VCS) for 23. Morphological analysis was performed with standard staining, histomorphometry and immunochemical staining for smooth muscle and endothelial cells. Vasomotor response was assessed using IntraVacularUltraSound with baseline luminal area and luminal area after injection of acetylcholine and nitroglycerin. Vasomotor response was assessed before suture and before removing the aorta. RESULTS: There was a significant improvement in operating time for closure with vascular staples (8 +/- 2 minutes versus 13 +/- 3 minutes) without thrombosis. We noted reduced intimal hyperplasia with staple closure (0.156 +/- 0.052 versus 0.087 +/- 0.042 mm, p<0.01). There was no difference for the medial thickness and the intima/media ratio was significantly different. The luminal area after suture was significantly better after vascular staple closure (16.78 +/- 0.639 mm(2) versus 17.24 +/- 0.492 mm(2), p=0.016). Vascular response to acteylcholine and nitroglycerin was equivalent for the two groups. CONCLUSION: Vascular closure staples are efficient for arterial closure. These non-penetrating systems prevent intimal hyperplasia and maintain physiological arterial vasomotor response.

[Non-Hodgkin's malignant lymphoma with parotid gland and ovarian localization]. / Lymphome malin non hodgkinien á double localisation glandulaire, parotidienne et ovarienne.

INTRODUCTION: Parotidean and ovarian lymphoma often indicate the existence of non-Hodgkin's lymphoma, involving 1-5% and 0.2% of the cases, respectively. EXEGENESIS: The authors report the case of a 70-year-old woman who presented B cell lymphoma of the parotid gland revealed by a rapid increase in the parotid size. CT scan showed the existence of a tumor located in the left ovary, later confirmed by biopsy. The proposed diagnosis was diffuse B cell type lymphoma with double glandular localization. Adenopathy and bone marrow involvement were both lacking. CONCLUSION: Lymphoma with glandular localizations always require diagnosis confirmation via histological examination and immunophenotyping, and must be considered as the local sign of a general disease.

[Littoral cell angioma: a rare vascular splenic tumor]. / L'angiome à cellules littorales: une tumeur vasculaire rare de la rate.

Littoral cell angioma is a rare primitive vascular tumor of the spleen considered as benign. Its clinical presentation is non specific. The diagnostic is based on histological and immunohistological analysis. The lesion is composed of anastomosing vascular channels often featuring papillary projections. They are lined by tumoral cells which exhibit an immunoreactivity for vascular and histiomonocytic markers. We report one case of littoral cell angioma and we discuss the diagnosis and the histogenesis of this tumor.

[Clear cell adenoma of the parathyroid gland: a rare and misleading lesion]. / Adénome parathyroïdien à cellules claires: une lésion rare et trompeuse.

Parathyroid adenomas are common lesions and are considered to be the cause of most of the primary hyperparathyroidism cases. We report the case of a 73 year-old man who presented with a primary hyperparathyroidism. Clinical and histological explorations revealed the presence of an isolated parathyroid tumor containing exclusively clear cells and devoid of malignancy. This is the second reported case of clear cell parathyroid adenoma. Thus, in spite of its low occurrence, this diagnosis must be considered after rejection of the most frequent parathyroid clear cell hyperplasia and parathyroid carcinoma, or depending of the location, clear cell thyroid tumor and clear cell renal carcinoma metastasis.