Primary Diffuse Large B-cell Lymphoma of the Lung

INCIDENTAL PRIMARY PULMONARY DIFFUSE LARGE B-CELL LYMPHOMA

Introduction: Gastrointestinal (GI) non-Hodgkin’s lymphoma (NHL) most often occurs due to widespread nodal disease with Diffuse Large B-cell lymphoma (DLBCL) being the most common subtype. However, primary GI NHL is rare, comprising of 1%-4% of all GI neoplasms. Even more rare is primary GI NHL arising from multiple sites within the GI tract. We present a rare case of a patient with primary DLBCL of both the antrum and duodenum. Case Description/Methods: A 55-year-old man with a past medical history of HIV/AIDS (CD4 83 cells/mm3, viral load 25250 copies/mL) and syphilis presented with generalized weakness, diffuse abdominal pain unrelated to oral intake, and peripheral lower extremity edema for the past few months. He endorsed having significant unintentional weight loss. Clinical examination revealed abdominal tenderness to palpation diffusely. Pertinent labs included hemoglobin of 6.9 g/dL (MCV 87.6), alkaline phosphatase of 472 IU/L, ALT of 16 IU/L, and AST of 35 IU/L. Both cytomegalovirus and Epstein-Barr virus viral load were elevated at 7796 copies/mL and 18200 copies/mL, respectively. Computed tomography angiogram of the abdomen revealed an enlarged gastric lymph node measuring 13 mm and irregular gastric thickening of the lesser curvature. Upper endoscopy revealed a giant ulcerated mass extending from the proximal body to the antrum with heaped up margins and an ulcerated necrotic base, in which biopsies were taken. There were also multiple duodenal nodules with biopsies taken. Pathology and immunohistochemistry of the gastric mass and duodenal nodules revealed primary DLBCL with positive CD10 cells and Epstein-Barr virus. After goals of care discussion, the patient was referred to Oncology for further therapy. Discussion: The GI tract is the most common site for extranodal secondary lymphoma. However, primary GI DLBCLs are rare GI malignancies. Our patient had primary GI DLBCLs in 2 different locations which is rarely seen in clinical practice. Primary GI DLBCLs can be easily missed as it can present with nonspecific symptoms as seen in our patient. When suspected, biopsies should be taken endoscopically to confirm lymphoma in addition to molecular analysis to accurately diagnose the lymphoma subtype for treatment guidance. Treatment of GI DLBCLs requires a multidisciplinary team including a gastroenterologist, oncologist, and a surgeon. Complications, such as perforation of the bowel, are common during surgical treatment.

BackgroundThe coexistence of non-Hodgkin’s lymphoma of the stomach and multiple primary lung adenocarcinomas with pulmonary cryptococcosis has rarely been reported.Case presentationWe herein present a 75-year-old man who was admitted to our hospital due to hematemesis. Gastroscopy and imaging revealed extensive stomach wall thickening and multiple lung lesions, including nodules and cavernous lesion. The patient was diagnosed with primary diffuse large B-cell lymphoma via gastroscopy and bilateral lung primary adenocarcinoma with cryptococcal infection via percutaneous CT-guided puncture biopsy. He subsequently underwent six cycles of R-CHOP regimen for gastric lymphoma, along with CT-guided radiofrequency ablation for the upper lobe of the right lung primary adenocarcinoma and radioactive particle implantation was performed on the lower lobe of the left lung primary adenocarcinoma, supplemented with antifungal therapy. After a definite diagnosis and systemic treatment, the patient was followed up for twenty-seven months with no tumor recurrence, progression or metastasis.ConclusionTo the best of our knowledge, the complex combination of multiple primary malignancies and pulmonary cryptococcal infection is extremely rare. The diagnosis is been confusing and challenging. CT-guided needle biopsy can help achieve pathological diagnosis, elucidate the type and stage of the tumor, and even change the clinical treatment strategy, which is necessary and beneficial.

Primary diffuse large B-cell lymphoma (DLBCL) of the colon, particularly involving the caecum, is rare and often poses a diagnostic challenge due to its non-specific presentation and the low incidence of colorectal involvement. Early recognition is crucial, as timely diagnosis and multidisciplinary management can significantly improve patient outcomes. A 29-year-old female presented with a two-week history of intermittent lower abdominal pain, progressive abdominal bloating, weight loss, night sweats, and bilateral ankle swelling over the last four weeks. Initial ultrasonography revealed a large soft tissue mass within the abdomen, initially reported as an ovarian mass; however, further evaluation, including CT imaging and colonoscopy, revealed an ulcerated, partially obstructing caecal mass. Histopathological examination of endoscopic biopsies confirmed DLBCL, non-germinal-centre B-cell subtype. PET imaging revealed multiple large, intensely fluorodeoxyglucose (FDG)-avid lymph nodes below the diaphragm forming a bulky nodal mass, along with a similarly FDG-avid caecal mass, strongly suggesting extra-nodal lymphoma involvement. The patient was subsequently managed with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone) chemotherapy under the guidance of a multidisciplinary team. Primary colonic DLBCL is rare, accounting for a small fraction of colorectal malignancies. Its non-specific symptoms, including abdominal pain, altered bowel habits, and constitutional complaints, can mimic more common gastrointestinal conditions. This case highlights the importance of maintaining a broad differential diagnosis, especially in younger patients. While imaging modalities, endoscopic assessment, and histopathology are critical for accurate diagnosis, prompt oncologic consultation and chemotherapy remain central to management. A multidisciplinary treatment approach is vital in improving patient prognosis.

Primary diffuse large B-cell lymphoma of the heart: A rare case of heart failure

Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomas mimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

#1183874: A Lump by Any Other Name: A Case of Primary Diffuse Large B-Cell Lymphoma of the Thyroid

Dear Editor: Epstein-Barr virus (EBV) is known to induce a number of malignancies, including diffuse large B-cell lymphoma (DLBCL) in immunosuppressed patients. Recently, however, age-related immune impairment was recognized as a predisposing factor in the development of EBV-driven lymphoproliferative processes in elderly patients1. Herein, we present a case of EBV-positive primary cutaneous DLBCL in an immunocompetent patient. A 66-year-old woman presented with a 6-month history of multiple erythematous macules and patches on her trunk and both extremities (Fig. 1). There was no specific past history except for hypertension. A skin biopsy was performed and histological examination of the specimen revealed multifocal and nodular infiltrates of atypical medium- and large-sized mononuclear cells with enlarged nuclei showing one or more prominent nucleoli (Fig. 2A, B). Immunohistochemical examination revealed that the tumor cells were positive for CD20, bcl-2 and latent membrane protein 1 (LMP1), but negative for CD3, CD5, CD10, CD30, and bcl-6. In situ hybridization for EBV-encoded RNA (EBER) was positive in the majority of tumor cells (Fig. 2C). Bone marrow biopsy revealed no lymphomatous involvement. Based on these findings, the patient was diagnosed with EBV-positive primary cutaneous DLBCL. She was treated with combination chemotherapy (R-CHOP) and reached complete remission. After a year, however, the disease recurred. She was treated with radiotherapy, but the disease progressed. Fig. 1 Multiple erythematous macules and patches were observed on her trunk (A) and both extremities (B). Fig. 2 (A, B) Skin biopsy revealed multifocal and nodular infiltrates of atypical medium- and large-sized mononuclear cells with enlarged nuclei showing one or more prominent nucleoli (HE A: ×40, B: ×400). (C) In situ hybridization ... Primary cutaneous DLBCL is a malignant proliferation of large B cells, presenting primarily in the skin with solitary or clustered erythematous or reddish-brown tumors. Histologically, dense diffuse infiltrates characterized by predominance of large cells with round nuclei are observed. Tumor cells express B-cell markers (CD20, CD79a). Most of the cases are positive for bcl-2 protein and multiple myeloma oncogene-1 (MUM-1), but are negative for CD10. EBV-related primary cutaneous DLBCL in non-immunocompromised patients is extremely rare. So far, only 11 cases have been reported1. All of the cases in the literature were of DLBCL except for 1 case. All of the cases of DLBCL occurred in elderly patients (over 55 years), presenting more frequently with multiple lesions at various locations. Many cases of DLBCL required combination chemotherapy, although one case underwent spontaneous remission1. Immunohistochemistry and in situ hybridization are the most important tests for the diagnosis of EBV-positive DLBCL. The tumor cells are usually positive for CD45 as well as for B-cell markers such as CD20, CD19, CD79a, and PAX-5. The cases are usually negative for germinal center markers, CD10 and bcl-6, and frequently positive for MUM-1. EBV-associated latent antigens such as LMP1 and EBNA-2 are positive in 94% and 28% of cases, respectively. Moreover, up to 50% of cases express CD30 but are negative for CD15. EBER in situ hybridization is the most reliable method for the diagnosis of EBV-positive DLBCL. It has the highest diagnostic sensitivity in the diagnosis of EBV-positive DLBCL2. So far, the prognosis of the newly recognized subtype of DLBCL remains in doubt, and there is no uniformly accepted treatment due to the small number of reported cases. On the basis of several literatures, EBV-positive DLBCLs seem to have worse response to chemotherapy than EBV-negative DLBCLs3-5. However, the response to rituximab-containing regimens has not yet been properly evaluated, and further studies are needed to clarify the role of rituximab and EBV-targeted therapy in EBV-positive DLBCL2. The proportion of EBV-related DLBCL cases in the elderly may be higher than that estimated at present. Therefore, we propose that EBV expression should be assessed in primary cutaneous DLBCLs. More information needs to be obtained regarding this new entity and further investigation is necessary.

Double-hit or dual expression of MYC and BCL2 in primary cutaneous large B-cell lymphomas

Primary pulmonary lymphoma (PPL) is an uncommon type of non-Hodgkin’s lymphoma. The majority of PPLs are of low-grade, mucosa-associated lymphoid tissue type. Primary pulmonary diffuse large B-cell lymphoma (DLBCL) is extremely rare, and prompt diagnosis may be challenging since its clinical symptoms and signs are nonspecific. Although the clinical features, diagnostic procedures, optimal management and prognostic factors of this disease have not yet been well defined, open thoracotomy and chest computed tomography (CT)-guided percutaneous biopsy are the preferred methods used in previous studies. In the present case report, the diagnosis and management of a patient with primary pulmonary DLBCL is reported. A 68-year-old patient was admitted to hospital in May 2013, with complaints of shortness of breath and intermittent wheezing and a cough associated with the production of small amounts of phlegm. Following admission, chest CT scans revealed a mass in the right middle lobe with ground-glass opacities at the lesion margins, as well as air bronchograms in the areas of consolidation. Bronchoscopy was performed and revealed an endobronchial lesion and partial stenosis in the distal end of the middle segment bronchus. Transbronchial needle aspiration (TBNA) of the right hilar lymph node, as well as endobronchial biopsy, was performed. The patient was diagnosed with primary pulmonary DLBCL by subsequent histopathological and immunohistochemical analysis of biopsy specimens collected via TBNA. Following the final diagnosis, standard treatment with CHOP chemotherapy resulted in significant clinical and radiological response and the patient remained in remission 8 months later. These results indicate that TBNA may be an effective method for the diagnosis of primary pulmonary DLBCL.

Primary gastric diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease entity that includes patients with (DLBCL/MALT) and without detectable mucosa-associated lymphoid tissue (MALT) lymphoma components (de novo DLBCL). We sought to evaluate the clinical characteristics and outcome of this disease in a large number of cases. Patients with primary gastric DLBCL (n=162) seen on 2001-2011 at the Tianjin Medical University Cancer Institute and Hospital and the First affiliated Hospital of Chinese PLA General Hospital were retrospectively reviewed. The distribution of sex, age, Lugano staging, and other main clinical characteristics was similar between the de novo DLBCL and DLBCL/MALT groups (p>0.05). However, the proportion of patients with a stage-modified international prognostic index (m-IPI) ≥ 2 was higher in the de novo DLBCL (34 %) than the DLBCL/MALT group (17 %) (p=0.026). In addition, the Helicobacter pylori infection rates were higher in the DLBCL/MALT (75 %) than the de novo DLBCL group (36 %) (p<0.001). Five-year progression-free survival (PFS) and overall survival (OS) estimates were similar for patients in the de novo DLBCL (p=0.705) and DLBCL/MALT groups (p=0.846). Surgical treatment did not offer survival benefits when compared with chemotherapy for 5-year PFS (p=0.607) and OS estimates (p=0.554). There were no significant differences in 5-year PFS and OS estimates for patients treated with rituximab-chemotherapy (p=0.261) or conventional chemotherapy (p=0.227). Non-GCB subtype and m-IPI ≥ 2 were independently associated with shorter OS, and advanced stages of lymphoma were independently associated with shorter PFS.

Objective To investigate the clinical features, diagnosis, treatment and prognosis of primary testicular diffuse large B-cell lymphoma. Methods 8 patients with primary testicular diffuse large B-cell lymphoma were reviewed from April, 2012 to April, 2015. The mean age was 58 years old, ranging 43-68 years old. Color Doppler echocardiography examination showed that there were round or oval regular tumors in the scrotum, which the diameter ranged from 3.5 to 8.0 cm, mean 5.5 cm. There was no abnormal changes among abdomen and pelvic cavity in CT scan and tumor markers examination. The radical orchiectomy were performed in all patients. After opening the tunica vaginalis, a hard texture tumor could be found, which has the vague border line with normal tissue. All patients were diagnosed according to the combination of morphologic and immunohistochemical examination after operating. Results All patients accepted operation successfully. The mean operation time was 34 minutes, ranging 25-40 minutes. 8 cases were diagnosed as primary testicular diffuse large B-cell lymphoma after operating. Immunohistochemical analysis showed that CD20, BCL-6 were positive.CD3, CD10, CK were negative. All patients received adjuvant chemotherapy with RCHOP(cytoxan 750 mg/m2, adriamycin 50 mg/m2, leurocristine 1.4 mg/m2, prednisone 60 mg/m2, rituximab 375 mg/m2) regimen over 6 cycles, which was conducted once every three weeks, one week post-operatively. The follow up duration ranged from 6 to 36 months, mean 17 months. All patients survived at the end of this study with no sign of recurrence and metastasis. Conclusions The patients with primary testicular diffuse large B-cell lymphoma are rare. The radical orchiectomy is recommended. And RCHOP chemotherapy should be considered one week post-operatively. The short term outcome of the treatment is satisfactory. But the long term outcome should be further studied. Key words: Testicular Lymphoma; Diffuse large B-cell; Prognosis

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), representing around 30% to 40% of all newly diagnosed lymphomas 1. DLBCL is clinically, morphologically and biologically a heterogeneous disease reflected in the highly variable clinical course. The 2008 World Health Organization (WHO) classification of lymphoid malignancies recognizes within the group of DLBCL, not otherwise specified (NOS) several subtypes characterized by unique clinical and pathological features including primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL, leg type, T-cell histiocyte-rich large cell lymphoma and EBV positive DLBCL of the elderly (Table 1). Nevertheless, most cases of DLBCL fall into the ‘NOS’ category. In the last 15 years our understanding of the genetic changes and biology of DLBCL has increased tremendously 2. Gene expression profiling (GEP) studies have revealed that DLBCL comprises several molecular subgroups that reflect either the stage in B cell development from which the disease originates or the activity of different biological programs 3, 4. The standard initial treatment for DLBCL is combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) 5. While durable remissions can be achieved in the majority of cases with this combined regimen, over 30% of patients will not respond or will relapse with resistant disease. A possible explanation for such differences in therapeutic success is the considerable biological heterogeneity of DLBCL. Therefore, there is an ongoing effort to tailor therapy based on specific subtypes of DLBCL, and to identify prognostic markers like BCL2 and MYC. The diagnosis of DLBCL needs to integrate, in addition to classic morphology and immunophenotype, all the new genetic and molecular diagnostic tools. This report attempts to review distinctive pathological characteristics of DLBCL and their clinical significance. DLBCL is characterized by monoclonal rearrangement of immunoglobulin heavy (IGH) and light chain (IGκ-IGλ) genes. Analogous to most B-NHL, DLBCL derives from a mature B cell that has experienced the germinal center (GC) reaction. Based on GEP studies DLBCLs have been divided into two main subgroups based on the putative cells of origin 3, 4. GC B cell-like (GCB)-DLBCL (50% cases) exhibits a transcriptional profile that resembles that of GC B-cell with expression of genes normally detected in GC B-cells such as CD10 and the transcriptional repressor BCL6 and harboring highly mutated immunoglobulin genes with ongoing somatic hypermutations (SHM). Activated B cell-like (ABC)-DLBCL shows several features of B cell receptor (BCR) activated B-cells at a plasmablastic stage, just prior to exit the GC with up-regulation of genes required for plasma cell differentiation (IRF4/MUM1) (Figure 1). These tumors downregulate the GC-specific program, activating at the same time, the NF-κB and BCR signaling pathways 2. Consistent with their late GC origin, these tumors do not show evidence of ongoing SHM. Because not all cases of DLBCL can be characterized as GCB or ABC, a less well-characterized group comprising about 15% of the cases remain unclassifiable. Within the group of mature B cell NHL, DLBCL shows the highest degree of genomic complexity including point mutations and copy number aberrations, and less frequently chromosomal translocations and gene amplification 2. Although some of these lesions might be observed in both GCB and ABC subtypes of DLBCL, most of them are preferentially associated with one or the other subtype of DLBCL, suggesting their potential role for diagnostic, prognostic and therapeutic stratification (Figure 2). The frequent mutations found in DLBCL are thought to be the result of an aberrant function of the physiologic SHM mechanism. Accordingly, mutations in CREBBP/EP300 and MLL2 are preferentially seen in GCB-subtype. EZH2 is required for GC formation and mutations in this gene are restricted to GCB-DLBCL. Translocations resulting in deregulated BCL2 and MYC are almost restricted to GCB-DLBCL. Around 30–40% of GCB-DLBCL carry the t(14;18) translocation, whereas MYC translocations have been identified in 5–15% of DLBCL 6. In contrast, translocations involving the BCL6 locus are present in 35% of DLBCL cases, being more frequent in ABC-DLBCL (25%). Another major transformation mechanism that impairs plasma cell differentiation are mutations and deletions in PRDM1/BLIMP1 identified in 25% of ABC-DLBCL. Constitutive activation of the NF-κB transcription factor complex represents the hallmark of ABC-DLBCL 2. The underlying causes of NF-κB signaling pathway activation are diverse and include gain-of-function mutations in signal transduction components of the BCR (CD79a and CARD11) and toll-like receptor (MYD88) signaling pathways. Loss-of-function mutation and/or deletions in the NF-κB negative regulator TNFAIP3/A20 have been reported in up to 30% of ABC-DLBCL. The diagnosis of DLBCL is usually not difficult. Lymph nodes demonstrate a diffuse proliferation of large lymphoid cells that have totally or partially effaced architecture. Cytological, DLBCL can be centroblastic, immunoblastic or anaplastic in appearance 1. Centroblastic morphology is the most common variant composed of medium to large cells with round to oval vesicular nuclei and fine chromatin with two to four nuclear membrane-bound nucleoli. There is moderate amphophilic to basophilic cytoplasm. In the immunoblastic variant greater than 90% of the cells have an immunoblastic appearance with a large centrally located nucleolus and basophilic or amphophilic cytoplasm. This variant has been associated with the non-germinal center type derivation, an adverse prognosis 4 and recently as a major reservoir for MYC-IGH translocations. In most cases, however; the tumors show an admixture of centroblasts and immunoblasts. The distinction of the immunoblastic variant from the centroblastic variant is not always straightforward and has generally met poor intraobserver and interobserver reproducibility. The anaplastic variant is rather rare and is characterized by large cells with bizarre pleomorphic nuclei. These cells may resemble Hodgkin or RS cells and may show sinusoidal and/or cohesive growth pattern and even mimic undifferentiated carcinoma. The anaplastic morphology is independent of ALK expression in B-cell lymphomas. Other rare morphologic variants exist including the signet ring cell, microvillous and spindle cell variants. The neoplastic cells characteristically express pan B-cell markers including CD19, CD20, CD22, PAX5 and CD79a. Surface and/or cytoplasmic immunoglobulin (IgM > IgG > IgA) can be demonstrated in 50–75% of the cases. Other markers commonly used in the characterization of DLBCL include CD10, BCL6, BCL2 and IRF4/MUM1 1. Aberrant phenotypes are not uncommon in DLBCL and may be responsible for confusion in the diagnosis. Lack of one or more B-cell markers may occur. In 10% of the cases the tumor cells express CD5. This CD5 positive DLBCL usually represent de novo cases, and only rarely are transformed CLL cases. Expression of CD5 is associated with worse prognosis even in the rituximab era. Aberrant expression of cytoplasmic CD3 has been also documented mainly in extranodal DLBCL without the expression of other T-cell markers. DLBCL with cyclin D1 expression lack the characteristic t(11;14) translocation of MCL, have a centroblastic morphology and a post-germinal center phenotype with positivity for IRF4/MUM1. These cases should be distinguished from MCL with blastic or pleomorphic morphology. In situ hybridization for EBERs should be performed in cases with geographic necrosis and/or Reed–Stenberg-like cells to exclude the possibility of an EBV+DLBCL of the elderly. Because of the prognostic value of cell of origin and the increasing effort to tailor therapy based on molecular characteristics of DLBCL, a reliable method to identify GCB and non-GCB subtypes is needed. GEP, which is considered the gold standard to assign the molecular subtypes, is not routinely available and is not cost effective in routine diagnosis. Several studies have attempted to recapitulate the molecular subgroups (GCB vs. non-GCB) using a limited panel of antibodies available in most pathology laboratories (Figure 1). The Hans algorithm has been the most widely used in clinical trials. In this classifier three antibodies are used CD10, BCL6 and IRF4/MUM1. According to this algorithm DLBCL with CD10 expression in more than 30% cells belong to the GCB group. Cases that are CD10 negative, BCL6 positive but IRF4/MUM1 negative are also GCB subtype. Cases that are IRF4/MUM1 positive with or without expression of BCL6 are assigned to the non-GCB subtype. There have been other algorithms attempting to improve the Hans classifier. These include the use of FOXP1 and GCET1 by Choi et al., and the use of LMO2 by Natkunam et al. One study comparing different algorithms showed an 87% concordance with GEP for the Choi method and 86% for Hans scheme 7. In this same study, the Tally algorithm based on FOXP1, GCET1, CD10, IRF4/MUM1 and LMO2 antibodies was demonstrated to be the most robust. The use of BCL6 was excluded from the analysis because it was considered a problematic, poorly reproducible stain. Nevertheless, in our experience BCL6 is reliable and helpful in the routine diagnosis. Accordingly, in the report from the international DLBCL rituximab-CHOP consortium program study, an algorithm based on expression of CD10, FOXP1 and BCL6 was used, which had a 92.6% concordance with GEP 8. Although most studies find that immunohistochemical algorithms correlate with prognosis in DLBCL, everybody agrees that these algorithms are an imperfect substitution for GEP. The improvement of molecular techniques is making possible to use paraffin-embedded material with results comparable to fresh-frozen material. The recent development of a 20-gene assay using NanoString technology in paraffin-embedded tissue is a promising methodology with potential to be used as a routine method for determining cell of origin in DLBCL 9. Translocations involving the MYC oncogene are the molecular hallmark of Burkitt lymphoma (BL). Most cases involve the IGH@ gene on chromosome 14. Less commonly, the light chain genes on chromosome 2 and 22 are involved in the translocation. These translocations in BL are characteristically the sole chromosomal aberration identified 10, 11. Approximately 5 to 15% of DLBCL cases have been reported to carry MYC translocations, whereas 19–38% of cases show MYC low copy number gains 6. Most MYC rearranged DLBCL cases fall into the GCB subtype 10, 12. In contrast to BL, MYC rearrangements in DLBCL are often seen to non-IGH@ partners and with complex karyotypes 10. The prognostic significance of MYC rearrangement alone in DLBCL is controversial. Several studies have demonstrated the association of MYC rearrangement with poorer outcome in DLBCL patients treated with R-CHOP 6. However, recent studies have suggested that the impact of MYC is strongly influenced by BCL2 and that MYC alone does not have a worse prognosis 13, 14. MYC rearranged DLBCL may either arise de novo or may represent a high-grade transformation of a low-grade lymphoma, usually follicular lymphoma. In the latter case the MYC translocation is accompanied by a BCL2 rearrangement, so-called ‘double-hit’ (DH) lymphoma. Approximately 40% of all DH lymphomas represent transformed FL cases 15. However, 60–80% of MYC rearranged bona-fide de novo DLBCL are accompanied either by a BCL2 and/or a BCL6 rearrangement, representing DH or triple hit (TH) lymphomas 12, 14. Altogether DLBCL with DH/TH represent around 3–6% of all DLBCL and are generally refractory to standard chemotherapy regimens and have a poor prognosis 13, 14, 16. Importantly, not all patients with DLBCL morphology and DH/TH may have a dismal prognosis. Recently, attention has focused on the apparent importance of the MYC partner because it has been suggested that only cases with an IG/MYC translocation have an adverse prognosis. The development of FISH assays readily performed in paraffin sections and more recently a monoclonal antibody that specifically recognizes MYC protein have facilitated the recognition of MYC alterations in routine diagnosis. Break-apart FISH probes are considered to be the most sensitive assay for identifying chromosomal rearrangements. In addition, the use of MYC/IGH dual fusion probe helps to confirm the MYC partner 6. However, dual fusion probes for MYC/IGκ and MYC/IGλ are not commercially available. MYC protein expression has been proposed as a rapid and cost-effective screening tool to identify MYC rearrangements. Although some studies agree that finding >70% MYC+ cells correlates with MYC rearrangement 6, 13, a considerable number of cases with MYC rearrangement fall into the low MYC expression group (<40%) 12. A combined approach MYC-FISH and IHC seems advisable. More common than MYC translocations is MYC protein overexpression reported to occur in 25–30% of DLBCL cases 13, 14, 16. Most studies used a cut-off of 40% for MYC positivity. Of note, the negative prognostic impact of MYC protein expression is observed only in patients who simultaneously overexpressed BCL2 protein, so-called ‘double-expresser’ (DE). The cut-off for BCL2 protein overexpression varies in different studies, but most studies required at least 50% of tumor cells. MYC and BCL2 DE have been reported to occur in 19–34% of DLBCL patients, and to have a worse prognosis than patients who do not express any or only one protein 13, 14, 16, but better prognosis than DH/TH DLBCL, which have a dismal outcome. Interestingly, the DE cases appear more common in the ABC subtype, and it has been suggested that this may largely contribute to the known inferior survival of the ABC subtype 16. The morphological distinction between BL and DLBCL has been problematic for pathologists. GEP studies have shown that BL has a characteristic signature but that there are cases within the spectrum of DLBCL and aggressive B-cell lymphomas, which have a similar molecular BL signature or fell into an intermediate category 10, 11. The 2008 WHO classification recognized this problematic an added a provisional category of B cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU) (Figure 3) 15. BCLU is a disease of older patients presenting with nodal or extranodal disease usually in an advanced clinical stage, high lactate dehydrogenase and frequent bone marrow and CNS infiltration with a dismal prognosis. Interestingly, MYC rearrangements can be detected in 30–50% of the cases usually associated with many more chromosomal aberrations 15. The incidence of DH/TH in BCLU has been reported to be high (32%–78%).The precise morphological boundaries of this category are still not well defined. There is an ongoing discussion about how to classify aggressive lymphomas with DH/TH. One proposal is to continue classifying them based on morphology as DLBCL or BCLU or putting them together as a group of ‘DH/TH lymphomas’ regardless of the morphology of the tumor cells. The understanding of the biology of DLBCL has increased tremendously in the last 15 years. The diagnosis of DLBCL needs to integrate, in addition to standard morphology and immunohistochemistry, all available ancillary techniques. The routine use of FISH and IHC to detect MYC and BCL2 alterations/overexpression is recommended. Patients with DH and double expression of MYC and BCL2 represent poor-risk subsets in which alternative strategies should be explored 5. The distinction of GCB versus ABC-DLBCL has not yet led to differences in primary treatment. The current standard of care for most patients is R-CHOP, which has improved dramatically the outcome of DLBCL. However, for patients who fail R-CHOP, the choice of therapy is very likely to be influenced by the cell of origin 5. For example, bortezomib or BTK inhibitors have been shown to be effective in relapsed ABC-DLBCL but not in GCB subtype. On the contrary treatment with EZH2 inhibitors and BCL6 inhibitors have been shown to be effective in relapsed GCB-DLBCL. Emerging new targeted therapy will certainly influence the diagnosis and treatment of DLBCL in the near future.

Rationale:Primary female genital tract lymphomas are sporadic neoplasms, accounting for 0.2% to 1.1% of all cases of extranodal lymphoma. The most common genital localizations are the cervix, the uterine corpus and the ovary, while primary lymphomas of the fallopian tube are quite unusual. According to literature searching in PubMed, this is the first reported case of primary diffuse large B-cell lymphoma of the fallopian tube.Patient concerns:A 52-year-old woman presented with a more than 2 months history of intermittent lower abdominal pain. The gynecological examination showed that the uterus, as big as 3 months of pregnancy, had weak activity and no tenderness. The uterine rectum lacuna was like a hard nodule of about 3 × 2 cm, and an irregular solid mass was fixed and inactive in the right adnexa.Diagnoses:In accordance with Ann Arbor staging system, a stage IE primary diffuse large B-cell lymphoma of fallopian tube was diagnosed for this patient, based on the tumor pathology, the results of bone marrow biopsy and computed tomography (CT) scan.Interventions:After gynecological/urinary ultrasound, blood test, pelvic contrast enhanced CT scan and CT angiography of iliac artery, exploratory laparoscopy and following hysterectomy with bilateral salpingo-oophorectomy were performed. After the surgery, the patient was treated with combined Rituximab and chemotherapy and got complete response (CR).Outcomes:After the operation and R-CHPOP, following up for more than 1 year so far, the patient has no tumor recurrence and is still in good condition.Lessons:It is very difficult to diagnose the primary diffuse large B-cell lymphoma of fallopian tube, not only because of its rarity, but also because of its non-specific clinical manifestations. It easily be treated as late ovarian cancer by gynecologist. So the pathology diagnosis and surgeons’ decision is very important. Because lymphoma is pretty sensitive to chemotherapy and easy to get complete response, so we no need to do an operation like ovarian cancer and should put chemotherapy as a primary method for lymphomas of the female genital tract.