1Mayo Clinic College of Health Sciences, University of Florida, Gainesville, FL 32611; 2Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL 32224
Intravascular large B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma characterized by neoplastic growth within the lumen of blood vessels. The disease is difficult to diagnose since the clinical symptoms presentations vary from asymptomatic to central nervous system manifestations and it carries a poor prognosis. Definitive diagnosis often requires multiple biopsies from various areas of the body. We present a case of intravascular large B-cell lymphoma involving capillary hemangioma localized to the spinal column in a 72-year-old male.
Intravascular large B-cell lymphoma; diffuse large B-cell lymphoma; hemangioma
Diffuse large B-cell lymphoma (DLBCL) is a lymphoid neoplasm characterized by abnormal growths of medium to large B cells. Although typically involving lymph nodes, tumors can form in extranodal locations and in various organ systems. It is estimated that up to 40% of DLBCL presents in extranodal sites [1]. Depending on the stage of the disease, DLBCL has been known to respond well to a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [2, 3]. This may be followed by radiation therapy or stem cell transplant depending on the severity of the disease [2, 3]. Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of DLBCL characterized by the growth of large, atypical B lymphocytes within the lumen of blood vessels [4]. The age-adjusted incidence rate of IVLBCL in the United States is estimated to be approximately 0.1 cases/million. It commonly presents in three different ways, known historically as the Western, Asian, and cutaneous variants [5]. The Western variant is characterized by neoplastic growth in the skin or central nervous system (CNS), whereas the Asian variant often presents with fever, thrombocytopenia, and bone marrow involvement [6]. The cutaneous variant is the least aggressive of the three variants, typically presenting as skin lesions with little to no systemic involvement [5]. Like DLBCL, IVLBCL is typically treated with R-CHOP and radiation, though the prognosis is not nearly as satisfactory. It is estimated that IVLBCL patients retain a 3-year overall survival rate of 11.5% compared to a much larger higher 70% overall survival rate of DLBCL patients in the rituximab treatment era [7, 8]. Given the aggressive nature of the disease, it is critical to understand the multifarious ways in which it presents in order to intervene at an earlier stage. Here we describe an interesting case of IVLBCL arising in a capillary hemangioma within the spinal column.
A 72-year-old male presented with worsening bilateral extremity and lower back weakness. Patient reported extreme lower body weakness to the point where he was unable to walk and wheelchair dependent. Notable past medical history included hypertension and hyperlipidemia. There was no reported history of blunt force trauma and no reported history or evidence of underlying immune deficiency. Physical examination did not reveal lymphadenopathy or skin rash/lesions. Laboratory testing at presentation included mild anemia and a normal white blood cell count and differential. LDH was within normal range at 127 U/L (reference range: 122-220 U/L). Infectious work-up including HIV, HSV, Hepatitis B/C, and bacterial and fungal cultures was negative. After initial evaluation by neurosurgery, the patient underwent a L2-S1 fusion, which resulted in very little improvement.
With worsening weakness, an MRI of the entire spine was performed and showed a 5.4 cm epidural mass causing dorsal compression of the thoracic spinal cord from T6-T8 (Figure 1). Additional MRI of the brain and CT of the chest were also performed and showed no evidence of intracranial lesions, adenopathy, or metastatic disease. A thoracic laminectomy and resection of the epidural mass was performed.
Resection of the T7 epidural spinal mass demonstrated prominent vascular proliferation with an atypical large cell infiltrate exclusively within the lumens of small and intermediate sized vessels (Figure 2). The large cells have irregular nuclei, vesicular chromatin, occasional prominent nucleoli, and moderate cytoplasm. The large cells express CD5, CD19, CD20, BCL2, BCL6, MUM1, and c-MYC. CD10 shows weak partial positivity and MIB-1 is >95% positive. CD138, kappa, lambda, EBV(EBER), and cyclin D1 are negative in the tumor cells. FISH for MYC rearrangement and MYD88L265P mutation analysis were negative. No additional cytogenetic or molecular testing was performed. Based on these findings, a diagnosis of IVLBCL involving capillary hemangioma was made. Bone marrow biopsy was not performed. Additional MRIs of the brain conducted four days after laminectomy showed no intracranial mass or pathologic enhancement.
The patient was started on therapy with rituximab, followed by a high dose of methotrexate, and then two cycles of R-CHOP. Chemotherapy was stopped due to a MRSA PICC line infection and bacteremia. The patient recovered well with a prolonged course of vancomycin. Due to a 6-month interruption in treatment, the patient was deemed unsuitable for continued chemotherapy. To date, the patient’s lymphoma is being treated with a combination of Bruton tyrosine kinase (BTK) inhibitor (ibrutinib), and rituximab infusions. MRI of the spine nine months after the initial diagnosis showed no signs of lymphoma mass recurrence. The patient was discharged back home to follow up with primary oncologist.
We describe a case of IVLBCL involving a capillary hemangioma which presented as an epidural spinal mass. Despite the aggressive nature of the disease, our patient was disease free nine months post therapy. To date, only a handful of cases of IVLBCL involving a hemangioma have been reported (Table 1). Hemangiomas are well known to be benign vascular tumors that arise in around 7% of adolescents and 75% of adults >75 years [9,10]. Like in the previously published literature, our patient’s age was consistent with the average age of most IVLBCL diagnoses [11]. Our case is unique in the presentation, presenting as growth within the spinal column rather than a subcutaneous lesion. In fact, the skin exam for this patient was unremarkable. Hirano et al [12] reported a similar case involving the CNS and with little noticeable skin involvement. In that case, a patient presented with right circumorbital pain found to be caused by a mass in the brain. Surgical resection of the mass demonstrated a cavernous hemangioma containing neoplastic B cells. Immunohistochemical analysis of the large lymphocytes was positive for CD20 and CD45, but negative for CD3, CD4, CD5, CD8, and CD30. Interestingly, our case shows CD5 expression. Prior literature has attempted to link CD5 expression to intravascular involvement, estimating that around 38% of IVLBCL cases express CD5 [13,14]. However, given the variable nature of this finding and rarity of the entity, this has yet to be further explored.
Over the past two decades, multiple studies have advocated for the biopsy of various skin lesions and hemangiomas for possible lymphomas, yet very few proved how and why IVLBCL appear to be drawn to hemangiomas [13,15]. Nixon et al [14] attempted to explain this, citing that lymphocytes of IVLBCL are incapable of transvascular migration due to the lack of CD29 and CD54 adhesion molecules. Satoh et al [16] also attempted to explain this relationship, stating that the lymphoma cells may get “trapped” by the vessel-rich structure of hemangioma, unable to proliferate elsewhere. Another explanation may be that hemangioma provides a place for neoplastic lymphocytes to remain undetected before proliferating throughout the body. In any case, this is still ambiguous and requires further investigation.
As far as whether treatments would change if IVLBCL was not localized to a hemangioma also remains unclear. Given the poor prognosis of this disease in general, treatments would likely remain the same (R-CHOP) to ensure no further metastasis of the disease. Based on our case and those reported in the literature, one might propose a subset of IVLBCL that are indolent in clinical behavior and carry a better prognosis; however, this is largely speculative. It is also possible that location, in this case hemangioma, may serve a protective function. At this time, this proves to be a likely hypothesis; however, further research is required to prove this theory. Although we were not able to perform more comprehensive genomic testing on this case other than MYD88L265P, recent genomic studies [20] confirmed the mutational landscape of IVLBCL which included mutations in PIM1, MYD88L265P, and CD79B, as a part of the B-cell receptor/NF-kB pathway, suggesting possible targets for novel therapy.
We present a unique case of IVLBCL arising in a capillary hemangioma. Given its overall poor prognosis, it is imperative to identify the disease at an early stage. While it is uncertain why some IVLBCL form within hemangioma, it may be a positive prognostic factor for these patients.
The authors declare that they have no conflict of interest.
