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Diffuse large B-cell lymphoma

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Diffuse large B-cell lymphoma
Jyoti P Mundi MD, Marie Leger MD PhD, Vitaly Terushkin MD, Max Fischer MD, Rishi Patel MD, Shane Meehan MD, Jo-Ann Latkowski MD
Dermatology Online Journal 18 (12): 25

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York


We present a 56-year-old man with a two-year history of erythematous nodules and plaques on the forehead, frontal aspect of the scalp, and left side of the neck. Histopathologic findings are compatible with a diagnosis of diffuse large B-cell lymphoma (DLBCL). We present a brief review of primary cutaneous DLBCLs and address the putative association between DLBCLs and hepatitis C virus infection.


Figure 1Figure 2

A 56-year-old man presented to the Bellevue Dermatology Lymphoma clinic with lesions on his head and neck. Two years prior he suffered a traumatic kick to the left neck and subsequently noted persistent swelling in the area. Six months later, he started to develop red lesions on his forehead. Review of systems was negative for pain in affected areas, fevers, night sweats, and weight loss. He has a history of hepatitis C virus infection but is otherwise healthy. With the exception of a multivitamin, he does not take any medications and denies any allergies to medications.

Physical examination

Multiple, erythematous nodules were present on the forehead, frontal aspects of the scalp, and left temple. There was an indurated, erythematous plaque on the left side of the neck in the distribution of cervical lymph nodes.

Laboratory data

The white-cell count was 4.5K/mm³. A comprehensive metabolic panel showed an elevated alanine transaminase level of 47 U/L and an alkaline phosphatase of 109 U/L. Lactate dehydrogenase level was normal. Rapid HIV 1/2 Antibody screen was non-reactive. Hepatitis B surface antibody and surface antigen were not detected. Hepatitis C viral RNA PCR showed 1,840,000 IU/ml (range: 4.30 – 69,000,000 IU/ml).

A bone marrow biopsy specimen showed a normocellular marrow for age with tri-lineage hematopoiesis and small lymphoid aggregates. A large B-cell lymphoma was not morphologically or immunohistochemically detected. Bone marrow aspirate flow cytometry indicated a minute population of aberrant CD5 (-) and CD10 (-) predominantly small cells, which were compatible with a B-cell-non-Hodgkin lymphoma. Differential diagnosis includes but is not restricted to marginal zone lymphoma. A definite morphologic correlate to the flow cytometry findings was not identified. However, the flow findings raised the possibility that the known DLBCL arose from a low-grade lymphoma.

Peripheral blood flow cytometry performed at an outside facility showed peripheral blood with no morphologic or immunophenotypic evidence of a lymphoproliferative disorder or presence of blasts.


Figure 3Figure 4

Below a Grenz zone, there is a diffuse infiltrate composed of sheets of large, atypical lymphoid cells with oval to irregular, hyperchromatic nuclei, some with prominent nucleoli, and moderate amounts of pale cytoplasm. With immunostains, these cells are diffusely positive for CD20 and CD79a, and focally positive for BCL-6. These cells are negative for CD5, CD10, BCL-2, and Cyclin D1.


Diffuse large B-Cell lymphoma (DLBCL) is a malignant proliferation of large B cells with varied morphology, phenotype, and molecular and clinical findings. It may develop de novo or arise from an indolent lymphoma and may be nodal or may involve extranodal sites [1]. The skin is the second most common site of extranodal non-Hodgkin lymphoma (NHL) after the gastrointestinal tract, with an estimated annual incidence of 1:100,000 [2].

Primary cutaneous B-cell lymphomas (PCBCLs) differ clinically and have a different prognosis when compared to histopathologically similar systemic lymphomas. The World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) defines PCBCLs as malignant lymphomas that are confined to the skin at presentation after complete staging procedures. PCBCLs comprise 10 to 25 percent of all primary cutaneous lymphomas and are categorized into four subtypes: primary cutaneous marginal zone B cell lymphoma, primary cutaneous follicular center lymphoma, primary cutaneous diffuse large B cell lymphoma-leg type (PCDLBCL-LT), and PCDLBCL-other [2].

PCDLBCL-LT presents as rapidly growing red or blue-red tumors on one or both legs and often occurs in elderly women. In 10 percent of cases, lesions occur at sites other than the leg. Histopathologic features of these lymphomas include a non-epidermotropic, diffuse infiltrate of centroblasts and immunoblasts in the dermis. Large cells usually predominate over small B cells and there are very few reactive T cells, mostly around the vasculature. A stromal component usually is absent. Immunophenotypically, the neoplastic B cells express B-cell-associated antigens, such as CD20 and CD79a, as well as bcl-2, bcl-6, and MUM-1/IRF4 protein [2]. Any primary cutaneous large B-cell lymphoma showing both bcl-2 and MUM-1 expression should be designated as PCDLBCL-LT independent of the anatomic site [3]. CD10 staining usually is absent. Translocations involving myc, bcl-6, and immunoglobulin H genes have been demonstrated. Chromosomal imbalances occur in up to 85 percent of cases. Inactivation of p15 and p16 tumor suppressor genes has been detected in 11 percent and 44 percent of cases, respectively [2]. The t(14;18)(q32;q21) chromosomal translocation, which leads to over-expression of the bcl-2 anti-apoptotic protein and is found in the majority of follicular lymphomas and in a lower percentage of systemic high-grade DLBCLs, is not found in PCLBCLs. The detection of a t(14;18) translocation in cutaneous B-cell lymphoma suggests the presence of systemic disease [4].

PCDLBCL-other refers to large B-cell lymphomas that arise in the skin and do not belong to the PCDLBCL-LT. This type includes cases that are morphologic variants of diffuse large B-cell lymphoma, such as anaplastic or plasmablastic subtypes or T-cell/histiocyte rich large B-cell lymphomas, which are usually a manifestation of a systemic lymphoma [2].

Although the presence of a B-cell lymphoma and hepatitis C virus (HCV) infection in our patient may be coincidental, two large US studies and an analysis by the European multicentre EPILYMPH consortium, have demonstrated an increased risk of NHL in patients with HCV infection as compared to HCV-negative controls. A meta-analysis of 15 case-control and three prospective studies showed a pooled relative risk of 2-2.5. The risk is most prominent in populations with high HCV infection prevalence, and this may indicate that there are other environmental factors that influence this relationship [5].

Although several lymphoma types have been associated with HCV infection, some epidemiologic studies have indicated a stronger relationship of specific subtypes with HCV infection, which includes DLBCL. There also are a few reports in the literature of PCLBCLs in patients with HCV infection [6, 7]. Large B-cell lymphomas in patients with HCV infection are thought to arise from an underlying low grade B-cell lymphoma, likely of the marginal zone type [5]. Our patient’s bone marrow flow cytometry raises the possibility that the known DLBCL arose from a low-grade lymphoma, which possibly is of the marginal zone type. Further research is necessary to characterize this association; however, chronic antigenic stimulation is postulated to play an important role in the expansion of polyclonal B-cells, which may then proceed to autonomous B-cell proliferation, immune dysregulation, and B-cell malignancy [5].

PCDLBCLs and systemic DLBCLs are treated with anthracycline-based chemotherapy [2]. Several studies have demonstrated that the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) increases the complete-response rate and prolongs event-free and overall survival in patients with diffuse large-B-cell lymphoma, without a clinically appreciable increase in toxicity. R-CHOP is now considered the standard first-line of treatment in patients with DLBCL [8].

Whether the presence of HCV infection is pathogenically relevant, it is most certainly of prognostic concern in our patient, especially in the setting of elevated transaminase levels at baseline. In a multicenter analysis, pretreatment transaminase levels were predictive of severe hepatic toxicity to treatment with R-CHOP chemotherapy. HCV RNA levels also increased appreciably during treatment [9].

The bone marrow biopsy specimen, flow cytometry, and imaging is currently being reviewed by our oncology colleagues to appropriately stage our patient’s disease. He is also currently preparing to initiate R-CHOP chemotherapy.


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8. Li X, et al. Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in China: a 10-year retrospective follow-up analysis of 437 cases from Shanghai Lymphoma Research Group. Ann Hematol 2011 Dec 9. Epub ahead of print. [PubMed]

9. Ennishi D, et al. Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood 2010;116:5119 [PubMed]

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