“Bone marrow–liver–spleen-type diffuse large B-cell lymphoma” presenting with cold autoimmune hemolytic anemia: a case report

Abstract

Introduction

Primary bone marrow diffuse large B-cell lymphoma is a rare clinical entity, and the “bone marrow–liver–spleen” type of diffuse large B-cell lymphoma is rarer, with only a few published cases in literature. Though bone marrow–liver–spleen-type diffuse large B-cell lymphoma has unique presentations such as fever, cytopenias, and hemophagocytic lymphohistiocytosis, no cases with cold autoimmune hemolytic anemia have been reported.

Case presentation

A 39-year-old Sri Lankan woman, previously healthy, presented with shortness of breath, productive cough, and fever for 4 days. Examination revealed pallor, icterus, and massive hepatosplenomegaly with no peripheral lymphadenopathy. Further investigation revealed pancytopenia (hemoglobin 58 g/L, white blood cell count 1.73 × 10⁹/L, platelets 23 × 10⁹/L, a reticulocyte index of 4.43%, and lactate dehydrogenase levels of 1690 U/L). Blood picture analysis was suggestive of hemolytic anemia, which was confirmed by a positive direct antiglobulin test with anti-C3d. The bone marrow biopsy revealed markedly hypercellular marrow with polymorphic infiltrate of mononuclear cells accounting for about 80–85% of nucleated cells. These cells were predominantly medium to large cells in size with scanty cytoplasm, irregular nuclear margins, prominent nucleoli, and many mitotic figures. These mononuclear cells were positive for immunohistochemical markers of CD20, BCL2, and CD10. The Ki-67 index was 24%. In addition, this patient had cold autoimmune hemolytic anemia. Contrast-enhanced computed tomography of the chest, abdomen, and pelvis revealed homogeneously enlarged liver and spleen with no significant lymphadenopathy. These findings were compatible with the diagnosis of bone marrow–liver–spleen-type diffuse large B-cell lymphoma. The patient was referred for specialized oncological management.

Conclusion

Though there are reported cases of primary bone marrow diffuse large B-cell lymphoma presenting with cold autoimmune hemolytic anemia, no such cases of bone marrow–liver–spleen-type diffuse large B-cell lymphoma have been reported. As this unique entity has a rather grim prognosis, it is of utmost importance to identify it early and treat aggressively. Owing to the limited availability of published accounts of this uncommon disease, we believe it is important to document our case to add to the understanding of this rare condition and its various presentations, which can easily be misinterpreted.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, accounting for almost 25–35% of cases [1]. Despite its prevalence, DLBCL is considered the catch-all category of malignant lymphomas, encompassing a wide variety of disease entities. The criteria for subclassifiying DLBCL include morphological variants, gene expression profiles, the expression of particular antigens, and primary anatomical sites of disease involvement [2]. DLBCL is an aggressive tumor that typically presents with rapidly enlarging lymph nodes or extranodal masses. Secondary bone marrow involvement occurs in approximately 10–16% of patients. However, bone marrow is an unusual site for the initial diagnosis of DLBCL [3]. DLBCL that primarily develops in the bone marrow (primary bone marrow lymphoma), with or without other organ involvement, but without lymphadenopathy, is quite rare and has been variably described in literature [4,5,6].

Bone marrow involvement by malignant lymphoma is generally considered as systemic dissemination of the disease originating elsewhere, such as the lymph nodes and extranodal organs. However, although extremely rare, malignant lymphomas exclusively involving the bone marrow, liver, and spleen have been reported. This distinctive but rare “bone marrow–liver–spleen” (BLS) type of DLBCL (BLS-DLBCL) has been recognized [7]. This lymphoma presents with involvement of the bone marrow, liver, spleen, often accompanied by severe anemia (100%), thrombocytopenia, hemophagocytic lymphohistiocytosis (HLH) (64%), and elevated lactate dehydrogenase (LDH) levels, in the absence of lymphadenopathy or other extranodal masses, and with no prior history of lymphoma [8, 9]. BLS-DLBCL appears to be a distinct clinicopathologic type of DLBCL with an aggressive clinical course and poor survival [7].

However, given that this type of DLBCL is not currently defined in the World Health Organization (WHO) classification, previous studies, which included different types of lymphomas, have been inconsistent in their reports of pathologic features and clinical outcomes. These previous reports seem to describe clinically similar lymphomas presenting with marrow involvement, categorizing them differently on the basis of additional sites of involvement (bone marrow only; spleen and bone marrow; or spleen, liver, and bone marrow) [7]. The lymphoma most similar to this entity is the WHO-defined intravascular large B-Cell lymphoma (IV-LBCL), at least from a clinical perspective [7]. Although it shares with intravascular LBCL a subtle presentation and an aggressive clinical course, this primary BLS large cell lymphoma variant is distinguished by lacking an intravascular component and having different cytogenetic findings [8].

Presentation of BLS-DLBCL typically includes classical clinical symptoms, cytopenias, liver–spleen involvement, and the more sinister hemophagocytic syndrome. We report herein a patient with BLS-DLBCL who presented with cold autoimmune hemolytic anemia (CAIHA) but did not fulfill the criteria for hemophagocytic syndrome. Given the limited availability of published accounts of this rare entity, it is crucial to document our case to enhance the understanding of BLS-DLBCL. This is the first known case that describes a varied presentation of CAIHA with BLS-DLBCL, expanding the spectrum of clinical manifestations and potentially aiding in early identification and treatment of this aggressive lymphoma.

Case history

We report the case of a 39-year-old Sri Lankan female who presented with BLS-DLBCL. She had shortness of breath, a productive cough, and fever for 4 days, with no significant past medical history. Examination revealed a subconjunctival pallor, tender hepatomegaly, and a massive nontender spleen extending 18 cm from the left costal margin with no peripheral lymphadenopathy.

Methods: differential diagnosis, investigations, and treatment

At the time of referral, the patient had hemoglobin of 7.2 g/dL, platelet count of 23 × 10⁹/L, white blood cell count of 3.6 × 10⁹/L, and neutrophil count of 1.05 × 10⁹/L.

Basic hematological investigations revealed pancytopenia: hemoglobin was 5.8 g/dL (Reference range:11–16 g/dL) with mean corpuscular volume (MCV) 81 pg (reference range: 80–100 pg) and mean corpuscular hemoglobin concentration (MCHC) 33.8 g/dL (reference range: 32–36 g/dL), indicating severe normochromic normocytic anemia, with thrombocytopenia of 33 × 10⁹/L (reference range: 150–450 × 10⁹/L) and leukopenia of 1.73 × 10⁹/L (reference range: 4–11 × 10⁹/L). The absolute neutrophil count was 0.7 × 10⁹/L (reference range: 2–7 × 10⁹/L). The reticulocyte index was higher than normal, at 4.43%.

The blood picture revealed leukoerythroblastosis with normochromic normocytic anemia, with many small red cell agglutinates. Many nucleated red blood cells, polychromatic cells, teardrop cells, and mild rouleaux formation were seen in the blood picture. Leukopenia was noted with few myelocytes. Some abnormal cells with prominent nucleoli and scanty cytoplasm were also observed.

The patient had normal levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) but increased total bilirubin (3.8 mg/dL; reference range: 0.2–1.2 mg/dL) with a predominance of indirect fraction (2.2 mg/dL; reference range: 0.2–0.8 mg/dL)). She also had an elevated level of LDH 964 U/L (reference range: 125–220 U/L). Serum haptoglobin level was not measured as it is not freely available in our country.

Moreover, the direct antiglobulin test was positive for anti-C3d specificity only, and cold agglutinin titer was performed, which confirmed the diagnosis of CAIHA (Table 1). The patient was initially managed by giving group matched (group A Rh D positive) 37 °C IAT cross-matched packed cell transfusions. Following 4 units of red cell concentrates, her hemoglobin increased to 9.5 g/dL and she became asymptomatic with stable hemoglobin. Though she had thrombocytopenia, she did not require a platelet transfusion, since there were no indications of bleeding manifestations or interventions.

Table 1 Results of cold agglutinin titer

Pathological findings: Following these findings, bone marrow aspiration was carried out but, after multiple attempts, resulted in dry taps. A trephine biopsy was later performed, which showed normal bone trabeculae with packed marrow spaces and overall cellularity was about 95–100%. A polymorphic infiltrate of mononuclear cells, accounting for about 80–85% of nucleated cells, was observed. These cells were predominantly medium to large sized with scant cytoplasm. Some cells showed irregular nuclear margins and prominent nucleoli. Many mitotic figures were present, with marked focal fibrosis. This led to the diagnosis of a high-grade lymphoma.

The formalin-fixed paraffin‑embedded tissue blocks were sectioned, deparaffinized, and rehydrated. Each section was stained with hematoxylin and eosin and used for immunostaining (Fig. 1A, B).

Fig. 1

Immunostaining of the bone marrow biopsy: A hematoxylin and eosin stain ×200 magnification, B hematoxylin and eosin stain ×400 magnification, C CD3, D CD20, E CD5, F CD10, G BCL2, H Ki67, I CD34

Immunohistochemical analyses were performed using an auto-stainer. The panel was found to be positive for CD20, CD10, and BCL2, but negative for CD3, CD5, and CD34. Ki67 index was found to be strongly positive. This confirmed the diagnosis of B-cell high grade lymphoma, most likely a diffuse large cell lymphoma involving in the bone marrow (Fig. 1C–I).

Radiological findings: A contrast-enhanced computed tomography scan of the chest, abdomen, and pelvis was performed to identify the primary focus of the lymphoma. It showed a homogeneously enlarged liver and a massively enlarged spleen with a maximum anteroposterior diameter of 13.3 cm. There was no evidence of paraaortic or significant lymphadenopathy in any other areas. No free fluid was noted in the peritoneal cavity. Since there was no evidence from presentations, clinical signs, blood investigations, and radiological images for other causes such as infections, hepatic malignancies, chronic liver cell disease with portal hypertension, and rare inherited disorders such as Gaucher disease for the patient to have massive hepatosplenomegaly, we considered that the liver and the spleen were involved with the lymphoma. The patient did not consent to a biopsy from liver or spleen to confirm the tissue diagnosis of lymphoma involvement (Supplementary File 01).

Outcome and follow-up

The patient was referred to the National Cancer Institute (NCI) Sri Lanka for further specialized oncological treatment and was successfully treated with R-CHOP chemotherapy cycles and is currently in remission. Though she required few red cell concentrates during initial presentation with CAIHA, later hemolytic anemia was resolved with the initiation of chemotherapy. There was no relapse of CAIHA during the follow-up period.

Discussion

BLS-DLBCL type is a distinctive and rare lymphoma with characteristic clinicopathological features and aggressive clinical behavior that has been relatively recently recognized. This lymphoma appears to be a distinct yet controversial entity that may represent a specific type of extranodal DLBCL [10]. In this manuscript, we describe an unusual and clinically aggressive extranodal large B-cell lymphoma involving the bone marrow, liver, and spleen (BLS-DLBCL) presenting with CAIHA.

The few cases reported with the diagnosis of BLS-DLBCL share a set of common clinical features. Patients typically present with fever and clinically or radiologically diagnosable hepatosplenomegaly, but no lymphadenopathy. Hematological investigations usually reveal anemia of unclear etiology, thrombocytopenia, and leukopenia, specifically neutropenia [7, 8, 11]. Our patient presented with a similar set of clinical symptoms, and investigations revealed pancytopenia. HLH has been reported in most cases, with variable prevalence ranging from 67–89% [7, 8, 12]. Although this patient exhibited a few clinical and laboratory criteria for HLH, they did not fulfill the diagnostic criteria. Despite this, our patient had CAIHA, which had never been reported in a patient diagnosed with BLS-DLBCL. Presentation of CAIHA has been reported in primary bone marrow DLBCL multiple times [13,14,15], but not in the more distinctive and rare BLS-DLBCL.

Increased levels of AST, ALT, and ALP have been reported in patients with primary bone marrow DLBCL and CAIHA, but our patient’s levels were normal [12, 14,15,16]. Bone marrow examination in our patient revealed a polymorphic infiltrate of large-sized centroblast-like lymphoid cells with a moderate amount of cytoplasm, large vesicular nuclei, and one to several prominent nucleoli, consistent with findings from other studies [8, 16].

Immunohistochemical studies across cases have shown strong positivity to CD20 and BCL2, as seen in our patient, while some cases revealed negativity for CD10 [13, 14] However, our patient showed positivity for CD10. The Ki67 index has been high throughout all reported patients, indicating high proliferative activity.

Conclusion

BLS-DLBCL is distinct enough to warrant recognition as a separate subtype, especially given its presentation, mimicking infection with hemophagocytosis, fever, and cytopenias, and its fulminant clinical course that is dramatically different from the more common DLBCL. It is important to keep an open mind in identifying these patients as early as possible as they can present with different clinical manifestations, as in our patient.