Relapsed Gray Zone Lymphoma: A Rare Clinical Challenge.

Gray zone lymphoma (GZL) is an extremely uncommon hematological cancer with characteristics in common with both classical Hodgkin's lymphoma (HL) and diffuse large B-cell lymphoma. In this case report, we present a rare case of a 22-year-old male who developed HL initially and then transitioned to relapsed or refractory GZL. The disease relapsed twice throughout, even after the peripheral blood stem cell transplant. The initial biopsy suggested it was classical HL, and the biopsy was done late in the progression of the disease; the features suggested it was GZL. The treatment consisted of curative and preventive chemotherapy, radiation therapy, and immunotherapy.

Stiff-person syndrome revealing an occult gray zone lymphoma: A diagnostic challenge.

Key Clinical Message: Stiff-Person Syndrome (SPS) can be associated with various malignancies, including lymphomas. Therefore, clinicians should always remain vigilant for the presence of an underlying malignancy, especially in older patients presenting with SPS. Abstract: Stiff-person syndrome (SPS) is a rare neurological disorder characterized by painful muscle spasms. It can occur as a paraneoplastic syndrome associated with various malignancies. We present a case of an older male adult with a history of recurrent fever episodes and elevated inflammatory markers for 1 year who subsequently developed neurological symptoms. The presence of positive amphiphysin antibodies led to the diagnosis of SPS, which prompted further investigations revealing an underlying Gray Zone lymphoma (GZL). This case highlights the challenges in diagnosing lymphoma and emphasizes the importance of considering SPS as a paraneoplastic syndrome in guiding toward the final diagnosis. The diagnostic challenge in our case is summarized in Chart 1.

Primary Mediastinal Gray Zone Lymphoma in an Immunocompetent Young Adult.

A 28 -year-old man presented to our hospital with a rapidly growing nodule in the left cervical and bilateral axilla with a history of loss of weight. He has been experiencing a nodule in her right cervical since two years ago and had done FNAC and diagnosed extrapulmonary tuberculosis (EPTB), on Examination at left cervical colli; mass size 9cm x 7 cm, mobile, Lymphadenopathy at pre auricular size 3cm x 3cm, lymphadenopathy supraclavicular size 1cm x 0,5 cm. bilateral lymphadenopathy Axila size 4cmx 4cmx 2xcm mobile. The other physical exam was normal. Laboratory test Hb 10,4 d/dL, WBC 14.250/ mm3, LED 78 mm/hours, D-dimer 1,81 ug/mL, Fibrinogen 452 mg/dL. HIV test non-reactive. HbsAg and HCV test negative. CT-Scan Thorax: Enlarged Anterior mediastinal Lymph node with a diameter 0f 2.9 cm, right paratracheal with a diameter of 1,2cm and 1,1 cm, and right perihilar with a diameter of 1,3 cm. and the left perihilar diameter 0,9. And hypodense lesion of the spleen measuring 2,3cm x 1,6 cm. The patient underwent a biopsy with pathology biopsy and immunohistochemistry (IHC), CD 20+. CD 3-, CD 30+ CD79a +, MUM1 +, Ki67 80-90% +, CD15-, BCL6+ and BCL 2+. For this patient, we started an R-CHOP regimen (Rituximab 375 mg/m2 (d1), Cyclophopamid 750 mg/m2 (d1), Doxorubicin 50 mg/m2 (d1), Vincristine1,2 mg/m2 (d1) and 1 Prednisone 100 mg (d1-d5). We presented the patient with PMGZL has achieved a complete response, especially with chemotherapy R-CHOP regimens.

Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed. The second half of the session focused on mediastinal and non-mediastinal gray zone lymphomas (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). Several cases illustrating the current challenges in separating this entity from PMBL/DLBCL and CHL were presented. There was discussion regarding the clinical and genetic differences between mediastinal and non-mediastinal GZLs. Rare cases of PMBL and GZL associated with EBV or follicular lymphoma were reviewed. Finally, several cases included in the session highlighted composite or sequential CHL and PMBL/DLBCL and/or GZL, highlighting challenges in separating such cases from GZL.

Mediastinal gray zone lymphoma in a pregnant woman presenting with cardiac tamponade.

BACKGROUND: Mediastinal gray zone lymphoma is a newly recognized rare B cell neoplasm, which is challenging in diagnosis and treatment. CASE PRESENTATION: In the current study, we aimed to report a 25-year-old pregnant woman at 25 weeks of gestation who presented with chronic cough and progressive shortness of breath, hypotension, tachycardia, and tachypnea. A large circumferential pericardial effusion with compressive effect on the right atrium and right ventricle and a large extracardiac mass with external pressure to mediastinal structures were seen on trans thoracic echocardiography. The emergency pericardiocentesis was performed with the diagnosis of cardiac tamponade. Also, CMR revealed a huge heterogeneous anterior mediastinal mass, and the pathology and the immunohistochemistry of the mass biopsy revealed gray zone lymphoma with positive CD3, CD20, CD30, CD45, PAX5, and negative CD15 expression. Three courses of chemotherapy with the CHOP regimen were performed with an acceptable response every three weeks before delivery. A caesarian section was performed at 37 weeks without any problem for the patient and fetus, and chemotherapy will be started three weeks after delivery. CONCLUSION: Cardiac tamponade as an emergency condition occurred in this pregnant patient by malignant pericardial effusion and mediastinal mass pressure. Accurate diagnosis and on time interventions caused a significant improvement and a successful delivery.

Pediatric gray zone lymphoma according to the 2022 WHO classification: An Italian cohort study.

BACKGROUND: The 2022 World Health Organization (WHO) classification redefines the concept of gray zone lymphoma (GZL), restricting it in practice to cases of mediastinal/thymic origin (mediastinal gray zone lymphoma, MGZL) with overlapping features between primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL). Cases with histological characteristics of GZL but occurring without mediastinal involvement are better classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), with few exceptions. PROCEDURE: We collected clinical and pathological data about all Italian pediatric patients diagnosed with GZL over a 20-year period. RESULTS: We identified only four cases of bona fide MGZL. All patients were adolescent and presented with a mediastinal disease, always associated with other nodal involvement. B symptoms and increased levels of both erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) were observed. Only two patients achieved a first complete remission, suggesting a more aggressive clinical behavior than either PMBCL or CHL. CONCLUSION: Prospective studies evaluating prognostic factors and establishing the most effective first-line therapy for MGZL are highly needed.

Internal Jugular Venous Thrombosis With Superior Vena Cava Syndrome: A Rare First Presentation of Gray Zone Lymphoma.

Gray zone lymphoma (GZL) is defined as a B-cell lymphoma with intermediate features between both diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (CHL). GZL is an aggressive disease, which in addition to the B-symptoms, can present as shortness of breath and neck swelling from underlying superior vena cava (SVC) syndrome. Thrombosis of the internal jugular vein (IJVT) is rare and usually associated with head and neck infection, intravenous (IV) drug abuse, and central venous catheter placement. GZL's initial presentation as IJVT with SVC syndrome is very uncommon. We report the case of a 47-year-old female presenting with neck swelling and shortness of breath. Initial investigations were oriented at the thyroid gland. A computerized tomography (CT) scan of the chest, neck, and head showed a large anterior/superior mediastinal soft tissue mass with left IJVT. An excisional biopsy of the left axillary lymph node confirmed the diagnosis of GZL. The mediastinal lymphoma can compress the internal jugular vein and also release thrombogenic substances that can cause IJVT. The compression of the SVC by the lymphoma and the IJVT formation can cause SVC syndrome. Both of these conditions can be life-threatening and should be identified in the early stages to prevent complications.

Hodgkin Lymphoma and Its Differential Diagnosis: New Twists on an Old Challenge.

Hodgkin lymphoma is a B-cell neoplasm that typically presents with localized, nodal disease. Tissues are characterized by few large neoplastic cells, usually comprising less than 10% of tissue cellularity, present in a background of abundant nonneoplastic inflammatory cells. This inflammatory microenvironment, although key to the pathogenesis, can make diagnosis a challenge because reactive conditions, lymphoproliferative diseases, and other lymphoid neoplasms may mimic Hodgkin lymphoma and vice versa. This review provides an overview of the classification of Hodgkin lymphoma, its differential diagnosis, including emerging and recently recognized entities, and strategies to resolve challenging dilemmas and avoid diagnostic pitfalls.

Brentuximab vedotin plus AVD followed by involved-node radiotherapy in a patient with classic Hodgkin lymphoma following gray zone lymphoma after autologous stem-cell transplantation failure.

BACKGROUND: No consensus has been reached yet concerning treatment strategies for a sequential classic Hodgkin lymphoma (CHL) following gray zone lymphoma (GZL). Prognosis of GZL after a failed autologous hematopoietic stem-cell transplantation (auto-HCT) is poor and treatment strategy is very limited. As yet there are limited data showing clinical outcomes of brentuximab vedotin (BV) for GZL, especially for sequential CHL after GZL. CASE PRESENTATION: We report a case of CHL following primary refractory GZL after a failed auto-HCT and showed favorable response to first-line CHL-directed chemoradiotherapy consisting of BV plus doxorubicin, vinblastine, and dacarbazin (AVD) followed by irradiation. The sequential cases with an early evolution, whose diagnosis of second lymphoma was made within a year, have been recently reported very poor survival shorter than a year. Whether a sequential CHL following GZL should be treated as a primary or relapsed disease has not been clearly elucidated. Our patient showed favorable response to first-line CHL-directed chemoradiotherapy without allogenic hematopoietic stem-cell transplantation and has in continuous remission for 2 years. CONCLUSIONS: The management of our case could help for physicians to make better treatment decisions and provide insights for further exploration in future studies.

Evolution in the definition and diagnosis of the Hodgkin lymphomas and related entities.

Hodgkin lymphoma was the first of the lymphomas to be recognized as a specific disease entity. However, recent studies have highlighted the heterogeneity of the diseases associated with this eponym warranting clarification and refinement of diagnostic terminology. While classic Hodgkin lymphoma (CHL) remains an essentially unchanged diagnostic entity in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is now renamed nodular lymphocyte predominant B cell lymphoma (NLPBL) in recognition of the distinct pathologic, biologic, and clinical differences. Fan patterns A, B, and C (sharing the presence of evident follicular structures, and retention of a B cell rich background) will be combined in "typical" or grade 1, while the other "variant" patterns, D, E, and F, are considered grade 2. T-cell/histiocyte-rich large B cell lymphoma (THRBCL) is considered part of the "variant" NLPHL continuum.The entity previously known as "B cell lymphoma, unclassifiable (BCLU), with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL" has been renamed "mediastinal gray zone lymphoma" (MGZL) in recognition of the importance of the thymic niche in the biology of this tumor. The diagnostic criteria for MGZL have been refined and require both a high tumor cell density and a strongly preserved B cell program.This article will describe updates on CHL, NLPBL, and MGZL in the recently published 2022 ICC and provide some useful differential diagnostic clues in cases with atypical morphology or immunophenotype.

Combined use of pathological and genomic alteration analyses for the diagnosis of gray zone lymphoma.

Histiocytic sarcoma (HS) is a rare malignancy showing morphologic and immunophenotypic features of histiocytes. HS has morphologic overlap with many other diseases, including various kinds of lymphomas. Gray zone lymphoma (GZL) is a rare B-cell lymphoma subtype characterized by overlapping features between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The histologic overlap with other diverse diseases of HS and the pathological diversity of GZL make it difficult to render a diagnosis. A 44-year-old woman who was initially diagnosed with HS was diagnosed with GZL after reexamination, including a genetic alteration test. After 6 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine, she achieved a complete response. Genomic alteration assessment may be useful for the accurate diagnosis of malignant lymphomas, which are difficult to diagnose, such as GZL.

Gray zone lymphoma effectively treated with cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab chemotherapy: A case report.

BACKGROUND: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (BCLu-DLBCL/cHL), also referred to as gray zone lymphoma (GZL), is known to share features with cHL and DLBCL. However, GZL is often difficult to diagnose. There is no consensus regarding the optimal therapeutic regimen. Most reported cases of GZL have been in Caucasian and Hispanic individuals, and its incidence is lower in African-American and Asian populations, including the Japanese population. CASE SUMMARY: A 69-year-old female presented at our hospital with a growing mass on the right side of her neck. An elastic, soft mass measuring 9 cm × 6 cm was palpable in the right cervical region. Laboratory analyses showed pancytopenia, increased serum lactate dehydrogenase levels, and markedly increased levels of soluble interleukin-2 receptor. Enhanced computed tomography (CT) and fluorodeoxyglucose positron emission tomography (PET)/CT revealed multiple lesions throughout her body. She was diagnosed with GZL based on the characteristic pathological findings, the immunophenotype [CD20+, PAX5+, OCT2+/BOB1 (focal+), CD30+, CD15-], and the strong positive expression of neoplastic programmed cell death protein ligand 1 (PD-L1) in her lymphoma cells. The lymphoma was stage IV according to the Lugano classification and high-risk according to the International Prognostic Index for aggressive non-Hodgkin lymphoma. The patient received cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (R-CHOP) chemotherapy because the tumor cells were CD20+. She has remained in complete remission for 3 years. CONCLUSION: GZL was diagnosed based on histopathology and immunophenotyping with ancillary PD-L1 positivity. R-CHOP chemotherapy was an effective treatment.

Comparative analysis of international prognostic indices in gray-zone lymphoma.

Gray-zone lymphoma (GZL) reflects an aggressive B-cell neoplasm with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). The International Prognostic Index (IPI) and its derivatives (R-IPI, NCCN-IPI, and the Hasenclever IPS) have been established for DLBCL or cHL while the most suitable scoring system for GZL remains undetermined. In an exploratory multi-centric cohort of GZL (n = 61), we performed a comparative analysis of prognostic indices with regard to model fit and mutual concordance. The calculation of the corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index) for each scoring system identified the NCCN-IPI to harbor the most convincing prognostic capabilities regarding both overall survival (OS) and progression-free survival (PFS) compared to its enhanced derivatives. The current results affirm the clinical utility of the NCCN-IPI and suggest its preferential use in clinical practice in GZL-patients.

How I Diagnose Primary Mediastinal (Thymic) Large B-Cell Lymphoma.

OBJECTIVES: Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is an uncommon large B-cell neoplasm recognized by the World Health Organization as a distinct entity on the basis of its unique clinical features, histogenesis, phenotype, and pathogenetic mechanisms. The diagnosis of PMBL can be challenging because of features that may overlap with other (Hodgkin and non-Hodgkin) lymphoma types. This review describes our approach to the diagnosis of PMBL. METHODS: Two cases are presented to illustrate how we diagnose PMBL and separate PMBL from related histologic and biological mimickers, such as Hodgkin lymphoma and gray zone lymphoma. RESULTS: A diagnosis of PMBL requires correlation of morphology and immunophenotype with clinical and staging data. Gene expression analysis is not typically performed in clinical labs but has expanded our understanding of the functional pathways underlying this disease and helped identify biomarkers that can be translated to diagnostic practice and possibly to future therapeutic options. CONCLUSIONS: PMBL and closely related entities can pose diagnostic challenges. It is important to understand the borders between PMBL and other closely related lymphoma types so that patients receive successful primary treatment with curative intent.

Transition Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma- Our Histopathological and Clinical Experience With Patients With Intermediate Lymphoma.

Even though information about the pathophysiology and clinical features of grey-zone lymphoma, an entity intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma, is growing, there are still a number of unanswered questions. The disease has no easily reproducible diagnostic criteria, which makes identification challenging. Uncommon, mixed histological picture and unusual clinical presentation should raise suspicion for grey-zone lymphoma. In this retrospective analysis we present 9 gray zone lymphoma patients, who were diagnosed in our institute between 2008 and 2018. The histological diagnoses was oftentime challenging, we asked for a revision in three cases due to the unusual clinical behavior and in other three cases only the relapse of the disease proved to be grey-zone lymphoma. Based on the initial histopathological diagnoses we applied adriablastine-bleomycine-vinblastine and procarbasine or cyclophosphamide-vincristine-adriablastine and prednisolon as first line chemotherapy regime with additional rituximab in six cases and brentuximab-vedotine in one patient. In six of the nine patients due to the primary refractory disease we used rituximab plus cisplatine, cytosine-arabinoside, prednisolone salvage treatment and five of these patients responded well enough to become eligible for autologous stem cell transplantation. One young male patient was refractory for various treatments and died due to the progression of his lymphoma. As a rare disease grey-zone lymphoma has no existing diagnostic criteria or guiedlines for its standard of care, which makes the everyday practice rather challenging for the clinicians, and emphasize the importance of unique decision making in every case and the repeated consultation between the pathologist and hematologist.

Aggressive Mediastinal Lymphomas.

The mediastinum contains essentially all major intrathoracic organs except for the lungs. A variety of both benign and malignant tumors can involve the mediastinum, of which lymphoma is the most common malignancy. Compared to secondary mediastinal involvement by systemic lymphomas, primary mediastinal lymphomas are less common with several specific entities that are mainly confined to mediastinal lymph nodes, and/or thymus. This review will summarize the clinical, histologic, immunophenotypic and molecular genetic features of the most common and most aggressive primary mediastinal lymphomas as well as provide suggested immunohistochemistry panels and differential diagnoses.

Brentuximab vedotin maintenance after autologous stem cell transplantation for refractory gray zone lymphoma with long-term remission.

Gray zone lymphoma (GZL) is a rare type of B-cell lymphoma characterized by features of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (cHL). The prognosis of GZL is poorer than that of cHL and mediastinal large B-cell lymphoma. However, an optimal treatment strategy for relapsed/refractory (R/R) GZL has not been established in the clinical setting. The current study reported an excellent clinical response in a patient with R/R CD30-positive GZL who received brentuximab vedotin (BV) maintenance after autologous stem cell transplantation (ASCT). Although the patient was resistant to prior treatments, BV maintenance after ASCT achieved long-term remission. Hence, BV was determined to be a safe and effective therapeutic option for CD30-positive R/R GZL.

Secondary cutaneous involvement by direct extension in high-grade B-cell lymphomas.

Cutaneous involvement by a systemic lymphoma via direct extension is a very rare phenomenon, historically described in patients who had advanced-stage disease with bulky lymphadenopathy. Since its original description, most cases of cutaneous lymphomatous spread via direct extension are attributable to Hodgkin disease. Here, we report the occurrence of direct cutaneous dissemination in the setting of nodal high-grade B-cell lymphomas, specifically diffuse large B-cell lymphoma (DLBCL) and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (also called gray-zone lymphoma). Both cases are adequately documented with clinical, histopathologic, and immunophenotypic data, as well as additional cytogenetic analysis.

Unraveling the Mystery of Gray Zone Lymphoma in Human Immunodeficiency Virus-Seropositive Patients: Two Cases.

Gray zone lymphoma (GZL) is an uncommon neoplasm with intermediate features of both classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). It was identified in the World Health Organization (WHO) classification as its own neoplasm in 2008. Patients infected with human immunodeficiency virus (HIV) have been rarely diagnosed with this type of lymphoma and treatment strategies for this subset of patients is not well described. Here we present two cases of patients with HIV that were diagnosed with GZL in a single community-based institution. A 68-year-old male with HIV/acquired immunodeficiency syndrome (AIDS) on highly active antiretroviral therapy (HAART) presented with 6-month history of dyspnea and weight loss. Computed tomography (CT) of the chest revealed multiple lung and mediastinal lesions, the largest measuring 9.4 × 5.5 cm lesion in the right perihilar region. Lymph node biopsy revealed abnormal lymphocytes with immunohistochemistry (IHC) positive for cluster of differentiation 30 (CD30), CD20 and Epstein-Barr virus (EBV), consistent with a diagnosis of GZL. The patient received dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) and attained a complete response. He since completed maintenance rituximab therapy and remains disease-free at 33 months. A 40-year-old female with HIV/AIDS on HAART presented with high-grade fever, dyspnea, and weight loss. CT imaging revealed multiple lung lesions, hepatosplenomegaly and diffuse lymphadenopathy in the chest and abdomen. Lymph node and bone marrow biopsy revealed cells positive for CD20, CD30, and EBV within atypical lymphoid cells. With this, a diagnosis of GZL was made and she was treated with DA-EPOCH-R. She attained a complete response and was on maintenance rituximab therapy. At 9 months she relapsed, she has now received a bone marrow transplant. GZL is a rarely described neoplasm within the HIV population. Here we describe two HIV patients diagnosed with GZL that were successfully treated at our institution. DA-EPOCH-R was able to induce durable remission with limited side effects and it represents a viable strategy for treating patients in this population. Further studies need to be performed to better characterize this lymphoma, especially in HIV patients. Treatment strategies for this select group of patients also need to be better defined.