Intravascular large B-cell lymphoma (IVLBCL):  Subtle Presentation and Challenging Diagnosis

doi:10.21203/rs.3.rs-3136830/v1

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Case Report

Intravascular large B-cell lymphoma (IVLBCL): Subtle Presentation and Challenging Diagnosis

https://doi.org/10.21203/rs.3.rs-3136830/v1

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Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive lymphoma defined by the proliferation of atypical lymphoma cells in the lumen of all sized blood vessels, particularly capillaries. The reasons for this unusual neoplastic cell proliferation are still only partially understood. IVLBCL is considered stage IV lymphoma and manifests with a variety of nonspecific signs and symptoms. Patients with IVBCL usually do not present with lymphadenopathy. The tumor cells invade the blood vessels of multiple organs such as the central nervous system, skin, lungs, kidneys, and bone marrow. Common presenting symptoms are based on the organ affected and include mental status changes and fever of unknown origin. Although immunochemotherapy has significantly improved the often-poor prognosis of this kind of lymphoma, a large percentage of patient’s relapse.

We present a 63-year-old man who had been diagnosed with high grade B cell lymphoma in the bone marrow in March 2021 and was in remission state after completing six cycles of chemotherapy. There was no abnormal FDG uptake on a post-chemotherapy PET/CT scan. Patient presented to the ER 1 year later with fever and dyspnea. The entire workup was completed and showed pancytopenia and elevated ESR. PET/CT scans revealed a widespread increase in FDG uptake in both the lungs and spleen. Lung biopsy revealed large, atypical cells only within alveolar septae and vessels that were positive for CD20 and PAX-5 and had high proliferation rate based on Ki67. The diagnosis of IVLBCL was made.

IVLBCL has a low incidence rate with non-specific clinical presentation. The diagnosis can be easily missed in both clinical, radiological and the corresponding histopathological findings. Radiological finding and CT scan are not sensitive enough and may miss the lesion. Even though the PET/CT scan is more sensitive, the definitive diagnosis of IVLBCL relies mainly on histopathology and immunohistochemistry, at which point awareness and high suspicious of this entity by the pathologist is most necessary.

Pathology

Intravascular large B-cell lymphoma

High grade lymphoma

Intravascular large B-cell lymphoma (IVLBCL), also known as intravascular lymphomatosis or angiotropic lymphoma, is a rare and distinct subtype of extranodal diffuse large B-cell lymphoma which has been revised in 2022 World Health Organization (WHO) classification of lymphoid neoplasms (1(. IVLBCL is a highly malignant and disseminated disease with uncommon clinical presentation and poor prognosis. It is characterized by the accumulation of tumor cells in the lumens of blood vessels especially capillaries, with little to no circulating neoplastic cells in the peripheral circulation (2). However, there are rare cases when proliferation in major blood vessels occurs (3). The underlying mechanism for this angiotropism is not clearly understood. The absence of adhesion molecules on tumor cells, such as b1 integrin, (ICAM-1) and metalloproteinases, is thought to alter the transvascular penetration of extracellular matrix for the tumor mass formation (4). IVLBCL can present with a wide range of clinical symptoms, such as unexplained fever, night sweats, anemia, weight loss, decreased cognition, and skin lesions. The diagnostic challenge of IVLBCL is mainly due to the fact that subtle histological changes could be easily overlooked, in addition to its rarity, non-specific and diverse clinical presentations, and lack of large mass lesions (5). The defining feature of IVLBCL diagnosis is the remarkable degree of sparing of the surrounding tissue along with the absence of tumor cells in the lymph nodes and reticuloendothelial system (6). R-CHOP chemotherapy (rituximab plus cyclo-phosphamide, hydroxydaunorubicin, vincristine, and prednisone) has significantly improved the previously dismal prognosis of IVLBCL. However, a substantial proportion of patients eventually experience relapse, particularly in the brain, and R-CHOP has minimal efficacy in these patients (7).

In this case report, we described the clinicopathological findings of a patient with IVLBCL.

We present a 63-year-old man who had been diagnosed with high grade B cell lymphoma in the bone marrow in March 2021 and was in remission state after completing six cycles of CHOP chemotherapy. There was no abnormal FDG uptake on a post-chemotherapy PET/CT scan. In March 2022, the patient started to have flu-like symptoms and he tested positive for COVID-19. However, his symptoms completely improved after 1 week. One month later, the patient presented to ER with high fever and dyspnea. The entire workup was completed and showed pancytopenia and elevated ESR. Chest CT scan did not show lymphadenopathy, or lesions, or mass within the lung. But PET/CT scans revealed a widespread mild increase in FDG uptake in both the lungs and spleen (Fig. 1 (A&B)). Lung biopsy was done and revealed large, atypical cells only within alveolar septae and vessels. Immunohistochemical stains demonstrated that these cells were positive for CD20 and PAX-5 and had high proliferation rate based on Ki67 (Fig. 2). The patient received two cycles of MATRIX chemotherapy with complete response. The patient was followed up every 3 months with PET/CT scan and until the time of writing this paper, the patient is in complete remission (Fig. 1 (C&D)).

Here, we report a patient who was diagnosed with large B-cell lymphoma in the bone marrow and achieved remission after completing six cycles of chemotherapy. However, 1 year later, he relapsed with lung and spleen involvement detected by a PET/CT scan and confirmed by immunohistochemistry.

This case highlights the difficulties of diagnosing IVLBCL, as imaging of the chest did not reveal any masses or lesions in the lung. Although the PET scan showed a mild increase in FGD activity with a SUV peak of 2.2, which is not normal but is low for a malignant tumor. Because the patient's dyspnea and fatigue worsened, the decision was doing a lung biopsy.

Initially, the H&E slides showed equivocal atypical cells only within the alveolar septae and vessels, which appeared to be reactive especially with patient’s recent history of COVID-19 (15). However, immunohistochemistry was performed, and the atypical cells were found to be positive for CD20 and PAX-5, and had a high Ki-67 proliferation index, leading to a diagnosis of high-grade B-cell lymphoma.

The disease's pathological characteristic is the luminal proliferation of tumor cells in small and medium-sized arteries without lymph nodes or peripheral blood involvement (10). The exclusive intravascular localization of malignant cells is supposed to result from the function loss of adhesion molecules required for tissue homing. Vascular occlusion can cause ischemic, hemorrhagic, or necrotic lesions in any organ, including the lungs, central nervous system (CNS), skin, kidney, or liver. The cause of the affected vessels' obstruction is still unknown. Endothelial surface damage may result in thrombotic microangiopathy, which causes platelet activation, thrombocytopenia, and red blood cell fragmentation, followed by the formation of microthrombi (9).

The clinical presentations of IVLBCL are various and non-specific. The symptoms are often related to organ dysfunction due to blood vessel occlusion, including fever, cutaneous lesions, neurological signs, hepatosplenomegaly, and pancytopenia. The neurological manifestation are often significant and are due to the presence of multiple infarct sites resulting from vascular occlusion. Although the cutaneous manifestations are vague, the most frequent symptoms are nodular, subcutaneous, firm masses or plaques with or without hemorrhage. Patients usually undergo multistep clinical investigations before the final diagnosis due to unpredictable and various clinical presentations. Unfortunately, some cases can be easily overlooked in routine histopathologic evaluation and are not diagnosed correctly due to the insidious intravascular growth pattern of IVLBCL cells (10).

Previously, there were two geographically distinct patterns of IVLBCL presentations (western and Asian forms). However, because of differences in the clinical features and outcome, three distinct types of variants (classical, cutaneous, and hemophagocytic syndrome-associated) have been described recently. The “cutaneous variant” is associated with a better prognosis as it is limited to skin lesions without other systemic involvement, and those patients have a 56% three-year survival rate; if it goes beyond the skin, that rate drops to 22% (10). On the other side, the worst prognosis form is the hemophagocytic syndrome-associated form, as it is associated with hemophagocytosis and multiorgan failure. According to the recently updated 2022 WHO classification, IVLBCL patients are classified into these three types based on their clinical features rather than their geographic distribution. In addition to these recognized variants of IVLBCL, other case reports highlighted atypical clinical features with challenges in diagnosis (11).

The heterogeneous clinical features of IVLBCL among patients make early diagnosis a challenge. Early diagnosis and early treatment might improve the outcome of IVLBCL. Many studies investigated the strategies for early diagnosis of IVLBCL, such as random skin biopsy, bone marrow biopsy, or FDG PET/CT. However, there has not yet been agreement on methods for early diagnosis of IVLBCL (8). Complete remission and long-term survival can result from aggressive combined chemotherapy (10). CT or MR imaging usually cannot establish the diagnosis of IVLBCL because there are few or no concomitant solid lesions (14).

The IVLBCL cell's origin has not yet been confirmed. There is a theory that IVLBCL originated from post-germinal center cells based on the presence of somatic mutations in immunoglobulin heavy chain variable region (VH) gene analyses (12). Nevertheless, other studies mentioned both germinal center (20%) and nongerminal center (80%) B-cell immunophenotypes. In 12–13% of IVLBCL cases, there is CD10 expression. Nonetheless, there are controversial results regarding CD10 expression and different clinical outcomes (10). Our findings in this patient support that the tumor cells originated from a germinal center B cell as there was an immunoreactivity for CD10 and PAX-5. Murase T et al. reported no significant difference between non-GCB and germinal center B cells (GCB) in clinical features or parameters of 96 IVLBCL cases (13).

Liquid biopsy is a promising method for diagnosing IVLBCL, but it is only available at institutions with the resources to analyze it (11). Anthracycline-based chemotherapy can improve the outcome of IVLBCL patients compared to those without any treatment based on many studies. The addition of rituximab to chemotherapy further improves the outcome of IVLBCL patients, but long-term survival remains dismal. Hence, there are trials to use more intense therapies, such as autologous hematopoietic stem cell transplantation (auto-HSCT). Some reports show longer survival times of treated IVLBCL patients with auto-HSCT, with three-year OS rates between 91% and 100%. Identifying the risk factors for IVLBCL patients with high relapse rates has not been determined. According to the findings of previous studies, auto-HSCT might be an option for a selected number of feasible IVLBCL patients (11). Untreated IVLBCL can be rapidly fatal (10).

In our case report, a patient previously diagnosed and treated for large B cell lymphoma in the bone marrow presented with fever and dyspnea. A PET/CT scan revealed abnormal FDG uptake lesions in the lung and spleen, and a lung biopsy revealed large atypical cells within alveolar septae and vessels. Immunohistochemical stains demonstrated that these cells were positive for CD20 and PAX-5 and had a high proliferation rate based on Ki67. FDG PET/CT scan may be valuable for the diagnosis of IVLBCL early. Consequently, for patients with suspected IVLBCL and without prominent skin involvement, FDG PET/CT can be considered a surveillance technique before biopsies (11). However, the definitive diagnosis of IVLBCL depends mainly on histopathology and immunohistochemistry.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Conflict of interest:

All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report.

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Intravascular large B-cell lymphoma (IVLBCL): Subtle Presentation and Challenging Diagnosis

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