Abstract
Background: A nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a lymphoproliferative neoplasm with a fair prognosis, but the possibility of a malignant transformation into a diffuse large B-cell lymphoma (DLBCL) is high. DLBCL progresses aggressively. Introduction of rituximab into therapy had led to improved outcomes. The use of Viscum album extracts (VAE) in cancer is established, but their application in lymphoma are rare. Case Presentation: A 65-year-old patient was diagnosed with DLBCL stage IIa with splenomegaly, transformed from a NLPHL, after a 30-year history of repeatedly enlarged inguinal lymph nodes. The patient initially rejected chemotherapy. After his tumor pain increased, he accepted the consecutive therapies bendamustine plus vincristine plus prednisolone, trofosfamide, and rituximab plus cyclophosphamide plus hydroxydaunorubicin plus vincristine plus prednisone (R-CHOP), inducing only a slight regression of the splenic lesions. VAE was additionally applied to R-CHOP. Five months after termination of chemotherapy — under continued VAE therapy in increasing dosage— regression of paraaortal lesions was found. The patient fully recovered under continuous VAE application and is in ongoing complete remission and in a good state of health 17 years after the initial diagnosis. Conclusion: As complete remission of lymphoproliferative disorders after VAE treatment has been previously reported, further investigations of VAE in lymphoma seem highly worthwhile.
- Diffuse large B-cell lymphoma
- Viscum album
- mistletoe
- nodular lymphocyte predominant Hodgkin's lymphoma
- malignant transformation
A nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a lymphoproliferative neoplasm with a fair prognosis, but transformation into a diffuse large B-cell lymphoma (DLBCL) is seen in 7.6% to 12% of cases after 10 years (1-3). DLBCL is aggressive when left untreated. Introduction of rituximab into CHOP-therapy (cyclophosphamide, doxorubicin, vincristine, prednisolone) has led to improved outcomes. However, patients with resistance to R-CHOP show a median survival of only 0.4 years (4). Huang reported in the Nebraska Lymphoma Study Group 7 patients with simultaneous and 14 patients with secondary transformation into a DLBCL after only one year (range=0.5-24 years); prognosis in these cases was poor with a median overall and disease-free survival of 35 and 11, months respectively (5). Patients with extra nodal lesions have a median survival time of only 16 months under multimodal chemotherapy with or without stem cell transplantation (5). We found no survival data about patients with a malignant transformation from NLPHL to DLBCL with resistance to chemotherapy.
Viscum album extract (VAE) is an aqueous extract derived from European mistletoe, a hemi-parasitic plant growing on different host trees (apple, pine, elm, oak and other trees). Commercial-injectable VAE preparations are available for supportive use in patients with cancer. VAEs are usually applied subcutaneously in an individually-adapted, dose-increasing schedule; however, intravenous and intratumoral applications, as well as intracavitary instillations, have also been reported (6). VAEs contain mistletoe lectins, viscotoxins, oligo- and polysaccharides, flavonoids, triterpene acids, and other pharmacologically active compounds. VAEs – and particularly their lectins – are strongly cytotoxic and induce apoptosis and increase cytotoxicity of chemotherapeutic agents (7, 8). They can down-regulate a variety of cancer genes involved in tumor progression, reduce cell migration, and interfere with tumor angiogenesis (9, 10). VAE and its compounds show strong immune stimulatory effects and neutralize the immune suppressive effects of tumors (11, 12). Clinical trials have found an improved quality of life in cancer patients treated with VAE (13); increased survival under VAE treatment has been reported in patients with advanced pancreatic cancer (14). Case reports and case series have documented the regression of different tumor types after application of VAE (6, 15, 16). Side effects include self-limited dose-dependent local skin reactions, flu-like symptoms, and occasionally allergic or pseudo-allergic reactions. Otherwise, VAE therapy is regarded as safe, even at higher doses (17). Clinical studies on VAE in patients with lymphoma are sparse compared to other tumor entities.
Case Presentation
A 65-year-old Caucasian male patient had a 30-year history of enlarged inguinal lymph nodes that were repeatedly investigated, only showing activated lymphocytes, reticulocytes, and granulocytes; ultrasound examination showed enlarged nodes in the right inguinal region of 2-6.8 cm. As the patient experienced increasing pain in the right inguinal region, a computed tomography (CT) scan was performed, showing increased nodes up to 9×6.2×5.6 cm in the right inguinal region as well as iliacal lymphoma enlarged up to 2 cm. Three months later, the patient underwent surgical excision of the right inguinal lesion, which had further increased in size to 11×10×9 cm. Histologically, the lesion showed areas of a NLPHL and areas with features of a DLBCL (Figure 1). In a following CT scan, splenomegaly of 15×13×8 cm was found with splenic lesions up to 2.5×3.5 cm; nodes were enlarged around the right A. iliaca externa and interna up to 2.5 cm and paraaortal up to 1.5 cm. The patient was diagnosed with a DLBCL stage II with splenomegaly, without B symptoms. He had a Karnofsky performance index of 70% (ECOG I) and lactate dehydrogenase (LDH) was elevated to 320 U/l (0-240) at initial diagnosis (International Prognostic Index (IPI) score 3). He had a normal body weight (68 kg, height 176 cm), and showed no signs of immune suppression. Further investigation showed no involvement of the bone marrow (aspiration biopsy of the sternum and iliac crest); beta-2-microglobulin was elevated to 3.4 μg/ml (1.1-2.4); and he had anemia (hemoglobin 12.9 g/dl).
Curative chemotherapy with R-CHOP with adjunct VAE treatment was proposed to the patient to increase the immune competency, reduce side-effects, and increase quality of life (18-20) and potentially reduce tumor growth (15, 21). The patient initially rejected these therapies, but in the following months, he experienced increasing pain in the upper abdomen and agreed to treatment with bendamustine, vincristine, and prednisolone (BOP). However, the treatment was stopped after 2 cycles due to increasing pain and decreased performance status. He accepted a palliative treatment with 3 cycles of Trofosfamide, but the tumor pain in the upper abdomen increased further during this therapy and opiates had to be prescribed. A CT scan showed that the paraaortal lymph nodes had increased to 6×6 cm and formed around the coeliac trunk and the Arteria mesenterica superior, compressing the retropancreatic vessels; abdominal tumor pain seemed to be caused by this tumor; splenomegaly was 16×13×7 cm with multiple lesions up to 5 cm (Figure 2). Six cycles of R-CHOP were applied with adjunct treatment with VAE (Figure 2). At the beginning of this therapy, beta-2-microglobulin was in the normal range (1.5 mg/l), the patient still showed elevated levels of LDH (363 U/l), anemia (hemoglobin 11.8 g/dl), and low but normal thrombocytes (146 cells/nl) and leukocytes (5.86 cells/nl); during the therapy granulocyte colony-stimulating factor had to be applied due to low leukocytes (0.8 cells/nl). After the sixth cycle, only minor tumor regression was seen (splenomegaly: no change; intrasplenic lesions: slightly regressed, paraaortal nodes: no change, iliacal nodes: partly regressed). No infections or fever occurred during the course of treatment.
The VAE treatment was started with a very low dose of 1 mg as subcutaneous injection 3 times per week concomitant to chemotherapy. The dose was increased 8 months later to 5 mg. Further augmentations to 10 mg, 20 mg, 30 mg, up to 50 mg (reached in December 2009) followed. The therapy was continued until December 2012. In increasing dosage, local self-limiting skin reactions <3 cm occurred; no other side effects were reported.
Five months after termination of chemotherapy and during ongoing VAE treatment, regression of the paraaortal lesions to 2 cm was found. Under continuous VAE application, a complete remission of all lesions was recorded after one year (spleen: 13×8.8×7 cm; intrasplenic tissue: homogenous; paraaortal nodes <1.9 cm; iliacal nodes <1.4 cm); the anemia, low thrombocytes, and high levels of LDH normalized within this period, and the patient had no pain and did not require use of analgesics. Subsequent follow-up investigations were performed with ultrasound, clinical examination, and laboratory tests every 3 months for the first 5 years and every 6 months after that. The patient is in ongoing remission and in a good state of health with a Karnofsky performance index of 100% and a body weight of 70 kg, 17 years after initial diagnose (for details of the course of treatment, see Figure 2).
Patient's tumor. Transformation of a NLPHL into a DLBCL. Two different infiltration patterns can be seen within the patient's tumor tissue: there are DLBCL regions (A-C) with a diffuse infiltration of medium- to large-sized blasts, that immunohistochemically show a diffuse reaction to the B cell-associated CD20-antigen; in these regions, there are scarce infiltrations of T-cells or histiocytes. Other regions (D-E) show an NLPHL with a mostly nodular tumor morphology with a diverse background of small activated lymphocytes, histiocytes and activated vessels. A: HE-stain 400×; B: CD20-stain 400×; C: Ki67-stain 400×; D: HE stain 400×; E: CD20 stain 400×. DLBCL: Diffuse large B-cell lymphoma; NLPHL: nodular lymphocyte predominant Hodgkin's lymphoma.
Informed Consent
Informed consent was received from the patient for the publication of the report. The patient read the submission version of the report and confirmed its content.
Antecedent and Concomitant Therapies
The patient had Gilbert's syndrome, hypertension, an asymptomatic mitral insufficiency, and cholelithiasis. During chemotherapy, the patient received bisoprolol for hypertension and bromazepam for paroxysmal anxiety attacks with tachycardia. The patient took nutritional supplements during chemotherapy including: selenium, zinc, magnesium, acerola tablets, and iron 14 mg per day. In the follow-up period after chemotherapy, the patient received 10 autohemotherapy treatments with ozone and local ointment application at the spleen containing 0.4% plumbum. No other anticancer treatment was given after termination of R-CHOP.
Discussion
In the case presented herein, the patient received palliative therapy with BOP, followed by trofosfamid and 6 cycles of R-CHOP. This treatment induced no tumor response (only slight regression of splenic lesions) and was stopped according to the patient's wishes. During the subsequent year, under sole VAE intervention in increasing dosage, all lesions of the lymphoma completely regressed. During this period, no other tumor-specific therapy had been applied. In this patient, the malignant transformation from NLPHL to a DLBCL had been confirmed histologically and reconfirmed for publishing this case.
Timeline of the patient and treatment.
The effects of VAE and its constituents on lymphoma cells have been investigated repeatedly: VAEs have been shown to be antiproliferative, cytotoxic, apoptosis-inducing and cell cycle – arresting (22, 23); they induced an increased lymphocyte infiltration of the tumor tissue, reduced neoangiogenesis and metastasis and enhanced survival in murine models (24-26). Additionally, the adoptive application of VAE-stimulated monocytes/macrophages induced tumor inhibition in mice with Ehrlich ascites carcinoma and mammary adenocarcinoma (27, 28). In human, smaller studies described remissions of non-Hodgkin-lymphoma (29). Three studies investigating safety found no risks of VAE treatment in Hodgkin's lymphoma and non-Hodgkin-lymphoma (30-32). Several case reports described durable tumor remission under VAE in malignant nodular lymphoma (21, 33, 34) and in cutaneous B-cell lymphoma (15). A complete remission of a pediatric nodal anaplastic large-cell lymphoma with cutaneous lymph proliferation under sole treatment with high-dose VAE was described (16). We therefore presume that VAE also contributed to the successful outcome of our patient.
However, regressions of DLBCL after months or even years after completion of R-CHOP also have been reported; Selenco et al. suggested a cross-priming of cytotoxic T cells to explain this phenomenon – tumor antigens from apoptosis during R-CHOP therapy led to an immune reaction with activation of cytotoxic T cells against the tumor tissue (35). Reports about spontaneous remission of a DLBCL transformed from an NLPHL couldn't be found in the literature. However, there are some cases about spontaneous remission of DLBCL (36). Spontaneous remissions are primarily explained by an induction of cytokines and stimulation of antitumor immune response of the host (36-38). This hypothesis is supported by remission after infections (36, 39, 40), the remission of MALT lymphomas of the stomach after eradication of Helicobacter pylori (41, 42), or remission after reduction of immune suppressive treatment (43-46) or the start of treatment of HIV infection (47). Infiltration with T lymphocytes has been observed after remission (37, 48, 49). A role of the tumor microenvironment is discussed as remission has been observed after biopsy (36), surgery (50), and injury (51). Remissions of malignant lymphoma have been induced by immunotherapy like active vaccination (immune peptides, DNA sequences, in situ vaccination), T cell stimulation, and modulation of the microenvironment (52). Taking all these together, lymphoma seems highly immunogenic as has also been seen in responsiveness to immunological treatment approaches as well as to VAE (38, 52).
Conclusion
Considering the immunogenicity of lymphoma, the immune-stimulating effects of VAE, and the course of the patient with resistance to immunochemotherapy and complete remission under increasing VAE therapy, we presume that VAE contributed to the positive outcome in this case. Late response to R-CHOP with induction of immunologic processes might have acted synergistically with the VAE therapy here.
This is only a retrospective report about a single patient, and no conclusion can be drawn from this and correlated to the treatment response of other patients. Therefore, VAE cannot replace current standard treatment for DLBCL. However, this case shows very interesting results regarding safety and possible effectiveness of VAE treatment in DLBCL. Further investigations seem worthwhile regarding this case and the current evidence about VAE use in lymphoma.
Acknowledgements
The Authors are thankful to the “Stiftung Integrative Medizin” for financial support. This case report was prepared following the CARE Guidelines (53).
Footnotes
This article is freely accessible online.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
- Received July 3, 2018.
- Revision received July 23, 2018.
- Accepted July 24, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
