Percutaneous Image-Guided Biopsy for Non-Mass-Forming Isolated Splenomegaly and Suspected Malignant Lymphoma

Background

The aim of this study was to evaluate the accuracy, safety, and role of splenic biopsy in the management of patients with non-mass-forming isolated splenomegaly and suspected malignant lymphoma.

Methods

Between 2001 and 2013, 137 biopsies were performed under computed tomography (CT) fluoroscopic guidance in 39 patients. All patients had splenomegaly based on the CT findings and a suspected diagnosis of malignant lymphoma based on their clinical symptoms. The spleen was the only accessible site to perform a biopsy, and no mass lesions could be identified in the spleen.

Results

The overall sensitivity, specificity, and diagnostic accuracy of image-guided biopsy for malignant lymphoma were 88%, 100% and 92%, respectively. Major complications occurred in 3 patients. In 1 patient, transcatheter arterial embolization was performed due to hemorrhage, and two patients needed blood transfusion because of hematoma development, without the need for further treatment.

Conclusions

Image-guided splenic core-needle biopsy is a safe and accurate technique with a high diagnostic accuracy in most patients who with non-mass-forming isolated splenomegaly and suspected underlying malignant lymphoma.     

Primary malignant lymphoma cutis.

Between 1934 and 1975, 16 patients with primary malignant lymphoma cutis were seen at the Ottawa clinic of the Ontario Cancer Foundation. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques. In all 16 the histopathologic diagnosis was diffuse non-Hodgkin''s lymphoma; 12 were considered to have prognostically bad lymphomas. However, the prognosis of primary malignant lymphoma cutis is significantly more favourable than is implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification.     

Correlation of anemia with infradiaphragmatic involvement in Hodgkin's disease and other malignant lymphomas

A staging laparotomy and splenectomy were performed in 41 patients with Hodgkin''s disease and 11 with other malignant lymphomas. There was a significant correlation (P = 0.025) between the presence of unexplained anemia and involvement of the spleen or abdominal lymph nodes by tumour. The anemias were of mild degree; hemolysis was documented in three and iron deficiency in four, while 21 cases were unexplained. Bone marrow was not involved by lymphoma in this series. The complication rate in exploratory laparotomy was higher than previously reported. Severe complications were observed in 17% of these patients while another 15% had minor complications. The association we have discovered may be helpful in the staging of patients who cannot tolerate an operative procedure. The absence of infradiaphragmatic involvement is suggested in the presence of normal hemoglobin concentrations.     

Cytologic diagnosis of intraocular lymphoma in vitreous aspirates

OBJECTIVE: To evaluate the cytologic findings of vitreous fluids with atypical, suspicious for malignancy or malignant lymphoid cells to assess cytologic parameters that may help in reaching the diagnosis of intraoclular lymphoma. STUDY DESIGN: Vitreous aspirates with a malignant, suspicious for malignancy or atypical lymphoid population were identified from the files of Barnes-Jewish Hospital during the previous 11 years. Cytologic preparations were reviewed. Pertinent clinical information was obtained from medical records. RESULTS: Thirteen vitreous aspirates from 12 patients were included. The chief complaints included floaters, blurred vision and decreased visual aculity. Bilateral ocular involvement was present in 8 (67%) patients. Three patients had a history of an extraocular lymphoid malignancy. All patients underwent pars plana vitrectomy and collection of the vitreous aspirate. Cytologic diagnoses included: malignant lymphoma (9 of 13), suspicious for malignant lymphoma (3 of 13) and atypical lymphoid population (1 of 13). Most samples had high cellularity (11 of 13) and necrosis (9 of 13). Abnormal lymphoid cells were large (2-4 times the size of a lymphocyte) and had a high nuclear/cytoplasmic ratio, prominent nucleoli, irregular nuclear contours and a fine to coarse chromatin pattern. All cases with malignant cytology had abundant abnormal lymphoid cells; inconclusive cases had few. Immunocytochemistry for CD20 and CD45RO was performed on 9 of 13 samples and was conclusive in 6 of 9. CONCLUSION: Cytologic analysis of vitreous aspirates can be useful in diagnosing intraocular involvement by malignant lymphoma. Sparse cellularity is the main factor leading to inconclusive diagnoses. Immunostaining can be useful in confirming the lymphoid nature of the malignant cells.     

Dermatopathic Lymphadenopathy—A Clinicopathologic Analysis of Lymph Node Biopsy Over a 15-Year Period

Forty cases of dermatopathic lymphadenopathy were found in a series of 906 consecutive lymph node biopsies (4.8 per cent).The histologic development and progression of the disease was correlated with the clinical state of the patient.In 35 of 40 cases the patients had active skin disease at the time of the biopsy; one of the remaining five patients had Hodgkin''s disease, one had multiple myeloma and one had secondary syphilis. In the other two, no organic cause was found.In nine cases (22.5 per cent), the histological pattern typical of dermatopathic lymphadenopathy was associated with malignant lymphoma. Except for two biopsies, which showed coexisting malignant lymphoma and dermatopathic lymphadenopathy, no histologic features were found which distinguished patients with malignant lymphoma from the remainder.While the pathogenesis of the lymph node changes remains obscure, the histologic features suggest that it is at least in part an immune response, although the nature of the responsible antigen is unknown.     

Immunosuppression during viral oncogenesis. IV. Generation of soluble virus-induced immunologic suppressor molecules

We describe herein functional attributes and generation of immunologic suppressor activity elaborated in response to oncogenic virus infection. Malignant rabbit fibroma virus-induced immunologic suppressor factor (VISF) is a T cell product produced in peak quantities by spleen cells taken from infected rabbits 7 days after infection in vivo. Its production does not appear to require macrophage participation. VISF is highly labile, 3.5 to 12 kDa, and capable of suppressing both B and T lymphocytic responses. Indomethacin and the cyclic nucleotides cAMP and cGMP inhibit its generation. VISF activity is neither antigen nor species specific. It suppresses murine and leporine immune responses to antigens unrelated to the inducing virus. Comparable suppressor activity may be induced by infecting an apparently non-functional rabbit T lymphoma line, RL-5, with malignant rabbit fibroma virus. VISF is principally a suppressor-inducer factor: in vitro, lymphocytes exposed to VISF do not show decreased immunologic responsiveness until 4 days of culture. VISF induces T suppressor cell activity when normal spleen cells are exposed briefly to VISF. Thus, immunosuppressive consequences of malignant fibroma virus infection are partially mediated by a small, non-specific T cell-derived suppressor lymphokine with unique functional characteristics. Non-specific immunologic dysfunction that often attends virus infections may reflect the activity of such factors in humans as well.     

Immunoregulation by Toxoplasma gondii infection prevents allergic immune responses in mice

Toxoplasma gondii is a ubiquitous intracellular parasite affecting most mammals including humans. In epidemiological studies, infection with T. gondii and allergy development have been postulated to be inversely related. Using a mouse model of birch pollen allergy we investigated whether infection with T. gondii influences allergic immune responses to birch pollen. BALB/c mice were infected with T. gondii oocysts either before or at the end of sensitisation with the major birch pollen allergen Bet v 1 and thereafter aerosol challenged with birch pollen extract. During the acute phase of infection, clinical signs correlated with increased levels of serum TNF-α, IL-6, IFN-γ and anti-Toxoplasma-IgM. In the chronic phase, Toxoplasma-specific serum IgG, brain tissue cysts and high IFN-γ production in spleen cell cultures were detected. Mice infected prior to allergic sensitisation produced significantly less allergen-specific IgE and IgG1, while IgG2a levels were markedly increased. IL-5 levels in spleen cell cultures and bronchoalveolar lavage fluid were significantly reduced, and airway inflammation was prevented in these mice. Notably, in mice infected at the end of the allergic sensitisation process, systemic and local immune responses to the allergen were markedly reduced. T.gondii infection was associated with up-regulation of Toll-like receptor 2 (TLR2), 4, 9 and 11, as well as T-bet (a differentiation factor for Th1 cells) mRNA expression in splenocytes; moreover, enhanced TGF-β, IL-10 and Foxp3 mRNA expression in these cells suggested that regulatory mechanisms were involved in suppression of the allergic immune response. Kinetic studies confirmed the induction of Foxp3⁺CD4⁺CD25⁺ regulatory T cells preferentially during the chronic phase of T. gondii infection. Our data demonstrate that T. gondii exhibits strong immunomodulating properties which lead to prevention of allergic immune responses and thereby support the hygiene hypothesis.     

Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder of unknown etiology and characterized by various clinical manifestations and multiple organ involvement. It has been reported in association with POEMS syndrome and can progress to Kaposi's sarcoma or malignant lymphoma. The disease runs a more aggressive course and a poor prognosis. Optimal therapies have not been well established up to now. We here reported a case of rare MCD complicated with multiple myeloma who received bortezomib and achieved very good remission. To our knowledge, this is the first report on MCD in the setting of multiple myeloma with good response to bortezomib.     

Hyperinfection Syndrome with Strongyloides Stercoralis in Malignant Lymphoma

Hyperinfection with Strongyloides stercoralis occurred in three patients with malignant lymphoma. The probable cause in each case was alteration of the immune responses either as a result of the malignant lymphoma or by the treatment given. Though thiabendazole (Mintezol) has produced reasonable results in the treatment of the hyperinfection syndrome, preliminary data suggest that the new broad-spectrum anthelmintic levamisole (Ketrax) is more effective. All patients who live or have lived in an area where strongyloidiasis is endemic should be investigated to detect the presence of the nematode before and during treatment with drugs with immunosuppressive properties. In view of the high mortality with S. stercoralis hyperinfection, vigorous therapy should be instituted before the use of immunosuppressive drugs.     

Psychological problems associated with diagnosis and treatment of lymphomas. II: Prospective study.

A prospective study of 120 patients newly diagnosed as having Hodgkin''s disease and non-Hodgkin''s lymphoma was conducted to determine the nature, extent, and timing of the psychiatric and social morbidity associated with the diagnosis and treatment. Patients were interviewed at diagnosis and two, six, and 12 months later by trained interviewers using standardised questionnaires. Psychiatric morbidity was greatest in the three months before treatment, but new episodes of anxiety and depression developed throughout the year of follow up. Altogether 39 patients suffered a depressive illness or anxiety state, or both, and a further 37 experienced borderline anxiety or depression, or both, during the 15 months of assessment. The most common adverse effects of treatment were hair loss, nausea, vomiting, sore mouth, and changes in perception of taste. Toxicity of treatment was associated with psychiatric morbidity. Conditioned responses to chemotherapy were experienced by 32 patients. Social morbidity was low, although difficulties in returning to work and to previous levels of leisure activity were noted. Although most patients were no longer receiving treatment and were free of disease at the one year follow up, 51 patients continued to complain of loss of energy, 24 of loss of libido, 38 of tiredness, 23 of irritability, 18 of poor concentration, and 23 of memory impairment. These results confirm our retrospective study and suggest that a high price is paid for long term survival by a substantial proportion of patients receiving treatment for Hodgkin''s disease and non-Hodgkin''s lymphoma.     

Cellular immunity to Hodgkin's splenic tissue measured by leucocyte migration inhibition.

Patients with lymphoreticular malignancy were shown by a leucocyte migration inhibition technique to have cellular immunity to Hodgkin''s splenic tissue. Migration was significantly inhibited in 31 out of 55 patients with Hodgkin''s lymphoma and 19 out of 39 patients with other types of lymphoma. Inhibition was also shown in only three out of 29 patients with other malignancy, one out of 23 normal volunteers, and one out of 25 patients with non-malignant disease. The splenic factor that inhibits leucocyte migration, which has yet to be isolated and identified, may be a helpful diagnostic tool in patients with suspected lymphoma.     

Opposing impact of AID deficiency on BCL-2 and IL-6 driven B-lymphoma development in BALB/c mice

Activation-induced cytidine deaminase (AID), an essential enzymatic activity required for somatic hypermutation and immunoglobulin class switch recombination in the course of normal B-lymphocyte development, has been implicated in the initiation and promotion of malignant B-cell tumors by virtue of a complex mechanism that includes the generation of oncogene-activating genomic rearrangements and the introduction of point mutations in cancer genes. Here, we use transgenic mouse models of B-cell lymphoma driven by the pro-inflammatory cytokine, interleukin 6 (IL-6), or the survival-enhancing oncoprotein, B-cell leukemia 2 (BCL-2), to evaluate the impact of loss of AID on neoplastic B-cell development. We show that AID deficiency accelerates BCL-2 induced lymphoma but delays IL-6 induced lymphoma. This led us to conclude that AID may function as tumor suppressor or tumor promoter, depending on the genetic context. Elucidating the mechanism of AID''s dual function during malignant B-cell transformation may be important for new approaches to tumor treatment and prevention.     

Risk of lymphoma in patients with dermatitis herpetiformis.

OBJECTIVE--To provide accurate estimates of the risk of lymphoma in patients with dermatitis herpetiformis. DESIGN--Comparison of observed and expected incidence of cancer in patients with dermatitis herpetiformis. SUBJECTS--976 patients aged 4 to 97 years with no clinical signs of coeliac disease who were admitted to hospital between 1963 and 1983. SETTING--Data from Swedish Cancer Registry. MAIN OUTCOME MEASURES--Incidence and type of cancer. RESULTS--106 cancers were diagnosed in 94 patients. The relative risk was 1.4 (95% confidence interval 1.1 to 1.7) in male patients and 1.2 (0.8 to 1.7) in female patients. When the individual cancer sites were analysed a significant risk was found only for malignant, non-Hodgkin''s lymphoma in male patients, with a relative risk of 5.4 (2.2 to 11.1). CONCLUSIONS--The risk of lymphoma is greater in male patients with dermatitis herpetiformis, and this calls for increased surveillance in these patients.     

Laparoscopy and laparotomy combined with bone marrow biopsy in staging Hodgkin's disease.

The relative merits of laparoscopy with liver and spleen biopsy and staging laparotomy were studied in 91 unselected patients with Hodgkin''s disease. Laparoscopy with liver and spleen biopsy were combined with needle biopsy of the bone marrow and laparotomy was combined with open bone marrow biopsy. In 65 untreated patients six out of seven with liver or marrow disease, or both, were shown to have extranodal lymphomas in these sites by laparoscopy plus needle marrow biopsy. Among 26 patients who had been treated this finding occurred in six out of 10 patients. Spleen biopsies during laparoscopy detected infiltration by lymphoma in 14 out of 37 (38%) patients with diseases spleens. Morbidity was higher after laparotomy than after laparoscopy. Laparoscopy produced abdominal bleeding secondary to splenic biopsy in two patients. All patients with Hodgkin''s disease should be subjected to laparoscopy plus needle marrow biopsy before undergoing laparotomy.     

Dendritic cells: Potential role in cancer therapy

Dendritic cells (DC) are extremely potent antigen presenting cells, uniquely capable of sensitizing naive T cells to protein antigens and eliciting antigen specific immune responses. Studies of human DC isolated from peripheral blood indicate that these cells can be used to stimulate and expand antigen specific CD4+ and CD8+ T cells, in vitro. On the basis of these findings we have initiated pilot clinical studies to investigate the ability of DC pulsed ex vivo with tumor associated proteins to stimulate host anti-tumor immunity when re-infused as a vaccine. In the first such study DC pulsed with tumor derived idiotype protein were infused into patients with low grade malignant B cell lymphoma who had failed conventional chemotherapy. The majority of treated patients developed T cell mediated anti-idiotype immune responses and some of the patients experienced tumor regression. These results suggest that DC based immunotherapy is a potentially useful approach to B cell lymphoma and raises the possibility that the approach may prove useful in the treatment of other tumors as well. This revised version was published online in June 2006 with corrections to the Cover Date.     

TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism

Toll-like receptor 9 (TLR9) triggering is a promising novel strategy to combat cancer as it induces innate and adaptive immunity responses. B-cell lymphoma is unique in this context as tumor cells express TLR9 and may harbor latent Epstein-Barr virus (EBV), a gamma-herpesvirus with remarkable oncogenic potential when latent. Latent EBV may be promoted by TLR9 triggering via suppression of lytic EBV. Here, we elaborated an initial assessment of the impact of TLR9 triggering on EBV-positive and EBV-negative B-cell lymphoma using Burkitt''s lymphoma (BL) cell lines as an in vitro model. We show that, independent of the presence of EBV, the TLR9 ligand oligodeoxynucleotide (ODN) CpG-2006 may or may not induce caspase-dependent cell death in BL cells. Moreover, ODN CpG-2006-induced cell death responses of BL cells were associated with TLR9 single-nucleotide polymorphisms (SNPs) rs5743836 or rs352140, which we detected in primary BL tumors and in peripheral blood from healthy individuals at similar frequencies. Thus, our findings suggest that the effect of TLR9 agonists on BL cells should be tested in vitro before installment of therapy and TLR9 SNPs in BL patients should be determined as potential biological markers for the therapeutic response to treatment targeting innate immunity.     

Latent anaphylactic sensitisation of infants of low birth weight to cows' milk proteins.

Latent systemic anaphylactic sensitisation to cows'' milk was assessed in 61 preterm infants who were randomly assigned to receive either a special formula for preterm infants based on cows'' milk or banked breast milk or one or other of these as a supplement to maternal milk. A single sample of venous blood was taken near to the time of discharge from the neonatal intensive care unit, and the histamine release by blood basophils in response to in vitro challenge with cows'' milk and anti-IgE was measured. Compared with the blood from infants fed on human milk, that from infants fed on preterm formula showed a significant increase in histamine release to challenge with cows'' milk, the response being greater in blood from infants of lower birth weight and gestational age. A smaller but significant increase in blood histamine release with anti-IgE challenge was observed in the group fed on preterm formula. Infants of low birth weight fed on preterm formula based on cows'' milk may develop latent systemic sensitisation more rapidly than infants born at term. The clinical importance of this requires further investigation.     

Intrathecal Chemotherapy in Burkitt's Lymphoma

Meningeal involvement with Burkitt lymphoma cells constitutes the most challenging therapeutic problem in the management of Burkitt''s tumour. The results of intrathecal chemotherapy with methotrexate or cytosine arabinoside in 55 episodes of malignant pleocytosis in 38 patients with Burkitt''s tumour are described. The response was complete in nearly all patients after the administration of either agent. Cerebrospinal fluid (C.S.F.) remissions were more prolonged in patients receiving intrathecal methotrexate or cytosine arabinoside daily for four days as opposed to a 10-day schedule. A controlled randomized trial of “prophylactic” intrathecal chemotherapy in patients without malignant cells in the C.S.F. on admission showed no protective effect against the subsequent development of malignant pleocytosis. Future therapeutic approaches are considered in the light of these results.     

Aldosteronism associated with adrenal cortical adenoma

Current trends in the search for chemical compounds having an inhibitory action on the growth of malignant cells are reviewed in this article. Several agents are sufficiently promising that clinical trials with them are in progress. One of these, an aromatic nitrogen mustard (C.B. 1348), appears to be useful as an adjunctive therapeutic measure in patients with malignant lymphoma, chronic lymphocytic leukemia, and mycosis fungoides who have become refractory to other methods of treatment. The introduction of certain purine antagonists, of which 6-mercaptopurine has been given the most extensive clinical trial, has opened up a new field of experimental and clinical investigation. 6-mercaptopurine and related compounds appear to be particularly useful in the treatment of acute leukemia in adults, but they are also useful, together with the folic acid antagonists and the steroid hormones, in the management of acute leukemia in children. While at present chemotherapeutic agents currently under investigation rarely cause significant regression of inoperable primary or metastatic solid tumors, the possibility of eventual more effective control in many types of malignant disease is not as dismal as it was a decade ago.