Infiltration Of Other Organs Research Articles

Abstract 6077: Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin

Abstract Adipose expansion during obesity has remarkable similarities with the growth of solid tumors. These similarities are the following: the capability to unlimited expansion; reversible plasticity; induction of angiogenesis; chronic inflammation; remodeling and disfunction; systemic influence on the organism; hormone production; production of miRNAs that influence other tissues; immunosuppression; DNA damage and resistance to apoptosis; infiltration in other organs and tissues. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors. Transgenic inducible zebrafish tumor model was used to verify the above hypothesis. We described several genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with human adipose. They are also involved in tumor development in humans. If the hypothesis of the evolutionary origin of mammalian adipose from the ancestral benign hereditary tumors is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors. Citation Format: Andrei P. Kozlov. Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6077.

Multiple Myeloma in a Feline

Background: Multiple myelomas (MM) are malignant neoplasms originating in the bone marrow plasmacytes, and are characterized by the presence of persistent hyperglobulinemia. Although they are rarely found in domestic animals, the canine species is most affected. In felines, they represent less than 1% of hematopoietic neoplasms, and mainly occur in older animals aged 10-12 years. The aim of the present study was to report a case of multiple myeloma, with extramedullary plasmocytosis in a feline.Case: A 3-year-old feline, female, mixed breed, with a history of apathy, anorexia, halitosis, and vomiting was referred to the Laboratório Regional de Diagnóstico (LRD) at the Universidade Federal de Pelotas (UFPel). Oral examination revealed a cyanotic oral mucosa and ulcerative lesions on the gingiva. The necropsy showed generalized lymphadenomegaly, splenomegaly, and hemorrhagic diathesis. Organ fragments were collected and fixed in 10% buffered formalin. After 48 h, the samples were cleaved, embedded in paraffin, and stained using the routine hematoxylin and eosin technique. Selected sections were subjected to immunohistochemistry (IHC) using the streptavidin-biotin method. The CD79a, CD138, CD3, and MUM1 antibodies were used. Histopathological evaluation of the bone marrow revealed hypercellularity with predominant round pleomorphic cells (90%), which presented an eccentric basophilic nucleus and abundant eosinophilic cytoplasm. The same neoplastic cells infiltrated the gingival mucosa, lymph nodes, spleen, liver, kidneys, heart, lungs, and brain. The IHC showed positive immunostaining for MUM1 and CD138 antibodies.Discussion: The diagnosis of MM in the present study was based on histopathology and by IHC. According to the literature, the presence of neoplastic plasmocytes in the bone marrow (>20%), osteolytic lesions, monoclonal gammopathy, and Bence-Jones proteinuria should be investigated in suspected MM cases. The presence of two or more of these characteristics is necessary for confirmed diagnosis. However, studies show that only 50% of felines with MM have two or more of these characteristics, with cell morphology and neoplastic infiltration in other organs being important parameters for the definitive diagnosis of MM in them. For MM diagnosis by IHC, CD79a, CD138, and MUM1 can be used. In this report, there was positive immunostaining for MUM1 and CD138, which allowed the exclusion of other neoplasms of hematopoietic origins. The origin of MM is unknown, but chronic immune stimulation is believed to be involved in humans. In felines, although infection by the feline immunodeficiency virus (FIV) and feline leukemia (FeLV) is commonly associated with the occurrence of lymphomas, the same is not described for MM. This was corroborated in the present study, since the animal in this report tested negative for FIV and FeLV. In cats, MM has no apparent predilection for race or sex, and mainly affects older animals (average age, 10 years). Although MM is rare, it has been described not only in this case, but also in young cats. The infiltration of neoplastic plasmacytes in the extramedullary tissues (extramedullary plasmacytosis) is observed more frequently in felines than in canines, and mainly occurs in the lymph nodes, spleen, and liver. In this case, there was disseminated extramedullary plasmacytosis involving multiple organs, such as the brain, lungs, heart, and kidneys. Persistent hyperglobulinemia is the main clinical manifestation of MM observed in 87.7% of cats with this neoplasm. However, this variation can also be observed in other pathologies, such as chronic lymphocytic leukemia, B cell lymphoma, primary macroglobulinemia, and chronic infections (e.g., ehrlichiosis, leishmaniasis, and heartworm disease). Hence, MM should always be considered as differential diagnosis when diagnosing the aforementioned diseases.

Conjunctival lymphomas in Japanese monozygotic twins: A case report.

An individual with a twin who has developed leukemia or non-Hodgkin lymphoma (NHL) has an increased risk of developing the same disease, particularly with monozygotic twins. The few reported pairs of twins who developed NHL had similar primary sites and pathological subtypes. Here, we present the first reported cases of primary conjunctival NHL in both female monozygotic twins. Twin 1 was diagnosed with an extranodal marginal zone lymphoma (EMZL; Ann Arbor stage IE) in the right conjunctiva at 25 years old and a subsequent tumor in the left conjunctiva at 39 years, and was also histopathologically diagnosed as EMZL. No infiltration of other organs was detected and both lesions were surgically excised. At the age of 40 years, Twin 2 was diagnosed with an EMZL (Ann Arbor stage IE) in the right conjunctiva without infiltration of other organs and was treated with external beam radiation therapy rather than surgery. Complete remission was achieved in both twins; neither developed conjunctival recurrences. This study highlights the importance of examining the other, apparently healthy twin when one twin develops conjunctival lymphoma.

Adipose tissue and liver.

Adipose tissue and liver are central tissues in whole body energy metabolism. Their composition, structure, and function can be noninvasively imaged using a variety of measurement techniques that provide a safe alternative to an invasive biopsy. Imaging of adipose tissue is focused on quantitating the distribution of adipose tissue in subcutaneous and intra-abdominal (visceral) adipose tissue depots. Also, detailed subdivisions of adipose tissue can be distinguished with modern imaging techniques. Adipose tissue (or adipocyte) accumulation or infiltration of other organs can also be imaged, with intramuscular adipose tissue a common example. Although liver fat content is now accurately imaged using standard magnetic resonance imaging (MRI) techniques, inflammation and fibrosis are more difficult to determine noninvasively. Liver imaging efforts are therefore concerted on developing accurate imaging markers of liver fibrosis and inflammatory status. Magnetic resonance elastography (MRE) is presently the most reliable imaging technique for measuring liver fibrosis but requires an external device for introduction of shear waves to the liver. Methods using multiparametric diffusion, perfusion, relaxometry, and hepatocyte-specific MRI contrast agents may prove to be more easily implemented by clinicians, provided they reach similar accuracy as MRE. Adipose tissue imaging is experiencing a revolution with renewed interest in characterizing and identifying distinct adipose depots, among them brown adipose tissue. Magnetic resonance spectroscopy provides an interesting yet underutilized way of imaging adipose tissue metabolism through its fatty acid composition. Further studies may shed light on the role of fatty acid composition in different depots and why saturated fat in subcutaneous adipose tissue is a marker of high insulin sensitivity.

Eosinophilic intestinal diseases of the horse

Summary Eosinophilic intestinal diseases of the horse are not commonly reported. Similar diseases are reported in man, but for either species, these eosinophilic diseases, are poorly understood. Eosinophilic intestinal disease may be accompanied by eosinophilic disease of other organs, or eosinophilia may be restricted to the intestine. When infiltration of eosinophils is restricted to the intestine, horses have a good prognosis for resolution of clinical signs, even though the treatment may include celiotomy with intestinal decompression or resection and administration of a corticosteroid. When eosinophilic intestinal disease is accompanied by infiltration of other organs, such as skin, pancreas, lungs or liver, the horse's prognosis for survival is very poor.

Ultrasonic features of pediatric eosinophilic gastroenteritis of children

Objective To summarize the manifestation of pediatric eosinophilic gastroenteritis by ultrasound and discuss the diagnostic value of ultrasonography in pediatric eosinophilic gastroenteritis. Methods The ultrasonic appearances of 31 cases of pediatric eosinophilic gastroenteritis confirmed by clinics and pathology were reviewed and analyzed. Results Nineteen of 31 cases were observed in association with eosinophilic infiltration of other organs which were diagnosed as idiopathic hypereosinophilic syndrome. Eosinophilic cystitis was the most common among the complications(89.4%, 17/19). Twelve of 31 cases were diagnosed as eosinophilic gastroenteritis without complications. The endoscopic appearances of eosinophilic gastroenteritis were nonspecific which include erythematous, hyperemia edema, and partiality erosion changes. Endoscopy demonstrates increased numbers of eosinophils in the propria of stomach and the duodenum. Ultrasound features of the gastroenteritis appeared diffuse or the parts of gastrointestinal tract. The most common sites of eosinophilic gastroenteritis were the stomach and duodenum.Involvement of muscle layer and serosal layer showed wall thickening of cyclic annular and uniformity. Ultrasound might show nodular or irregular thickening of the folds in the gastric antrum when the submucosa were thickening. The mucosal layer involvement was not easy to be found by ultrasound. The echo of serous layer and submucosa associated with the disease stage. The thickening of surrounding omentum and mesenteric tissue, echo enhancement and nonspecific hyperplastic mesenteric lymph nodes infiltrated with eosinophils might be present.Eosinophilic ascites could often be detected. Conclusions Ultrasound has obvious advantages in the diagnosis of pediatric eosinophilic gastroenteritis, and the ultrasonic changes of pediatric eosinophilic gastroenteritis are characterized. Ultrasonography can provide the possible diagnosis when combined with inflammatory of other organs, especially cystitis inflammatory changes. Key words: Ultrasonography; Pediatric; Eosinophilic gastroenteritis

P11.08 * CENTRAL NERVOUS SYSTEM LYMPHOMA IN A PATIENT WITH MYCOSIS FUNGOIDES

Mycosis fungoides (MF), the most common malignant T-cell lymphoma of the skin with an annual incidence of 4.2 cases per million in the United States, usually evolves slowly over many years. Extracutaneous manifestations of MF are observed in 50-75% of cases, typically occurring in patients with advanced infiltration of other organs. The incidence of central nervous system (CNS) involvement in MF was reported to be 14% in autopsy series and less than 1.6% in clinical cohorts particularly in patients with large-cell transformation of MF. A 67-year-old woman was diagnosed with plaque stage MF in 1990 after having developed disseminated, well demarcated, erythematous macules and plaques on the trunk. The patient reported that psoriasiform skin lesions had been present over the past 35 years. Treatment consisted of topical corticosteroids, systemic psoralen plus ultraviolet A, acitretin and interferon, resulting in a complete remission since 2007, without further treatment. In April 2013, the patient presented with a 2-month history of cognitive deficits and bifrontal headache, followed by rapidly decreasing visual acuity with central and peripheral visual field defects. Magnetic resonance imaging (MRI) showed thickening of the optic chiasm and both optic nerves with homogeneous contrast medium enhancement and space-occupying effect on the hypothalamus. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis of 107 cells/µl, no lymphoma cells were detected, CSF protein was elevated (116 mg/dl), glucose and lactate were normal. A subsequent brain biopsy confirmed the diagnosis of a diffuse large-cell lymphoma of the B-cell type. Despite preoperatively started dexamethasone treatment the patient experienced severe visual loss. Following 4 cycles of chemotherapy containing high-dose methotrexate and cytarabine according to the IELSG protocol and 2 cycles of methotrexate monotherapy from May until October 2013, clinical examination showed marked visual improvement, consistent with almost complete resolution of the MRI abnormalities. Due to pituitary gland insufficiency the patient needs further hormone replacement therapy. This case illustrates the importance of considering CNS lymphoma in the context of MF, even after long-term remission of the disease limited to the skin. To the best of our knowledge, this is the first description of a primary CNS B-cell lymphoma secondary to MF.

T4N0 Colon Cancer Has Oncologic Outcomes Comparable to Stage III in a Specialized Center

National data indicate that patients with T4N0 colon carcinoma have worse oncologic outcomes than other stage II cases. Our hypothesis was that optimized surgical resection and lymph node staging in a specialized center could eliminate discrepancies in oncologic outcomes within stage II colon carcinomas. Patient characteristics and outcomes after oncologically radical colectomy for pT4N0 were compared to control groups of T1-2N1, T3N1, and T3N0 cases. Group comparisons were adjusted for age, American Society of Anesthesiologists score, tumor location, year of surgery, and duration of follow-up. Cases with at least 12 collected lymph nodes and uninvolved resection margins (R0) were analyzed separately. In addition, the T4a subgroup was compared to both T4b cases with involvement of bowel loops and with infiltration of other organs or structures. T4N0 patients had worse oncologic outcomes than T1-2N1 patients and were comparable to T3N1 patients, regardless of margins status or lymph node collection. When a T4b tumor infiltrated bowel, survival and recurrence rates were similar to T4a cases, while T4b tumors involving other organs were associated with increased recurrence rate and reduced survival. T4N0 colon carcinoma remains associated with poor oncologic outcomes, regardless of treatment in a specialized center. The biologic aggressiveness of T4N0 colon cancers and the different oncologic outcomes according to specific organ infiltration should be taken into consideration in the choice of adjuvant therapies.

Rationale and efficacy of interleukin-1 targeting in pediatric Erdheim- Chester disease

Erdheim-Chester disease (ECD) is a rare non-Langerhans systemic histiocytosis of unknown origin. ECD is characterized by bilateral and symmetric sclerosis of the metaphyseal regions of the long bones and infiltration in other organs. Histopathologically, ECD is characterized by a mononuclear infiltrate of foamy histiocytes.

Eosinophilic cystitis associated with eosinophilic enterocolitis: case reports and review of the literature

We report three cases of eosinophilic cystitis. Contrast-enhanced computed tomography (CT) revealed characteristic bladder wall thickening exceeding 10 mm, with preservation of the mucosal lining and intense, progressive contrast enhancement on sequential arterial and delayed scans. Eosinophilic cystitis might have been associated with eosinophilic infiltration in other organs, such as the gastrointestinal tracts and liver.

Erdheim-Chester Disease in Childhood

Erdheim-Chester disease is a rare, non-Langerhans systemic histiocytosis characterized by bilateral sclerosis of the metaphyseal regions of the long bones and infiltration in other organs. The histopathologic hallmark is defined by a mononuclear infiltrate of foamy histiocytes and rare pathognomonic Touton giant cells with extensive fibrosis. This condition is exceptional in children. We report here a case of Erdheim-Chester disease in a 10-year-old girl with retroperitoneal infiltration and bone involvement, for whom the diagnosis was only established after a 3-year course with multiple biopsies. It is also the first pediatric case successfully treated with interferon-alpha suggesting that interferon-alpha can be a safe and efficient first-line therapy for this disease in children.

CXCR4 Antagonists Mobilize Acute Lymphoblastic Leukemia Cells into the Peripheral Blood and Inhibit Engraftment in Mice.

The role of CXCL12 in the growth of B cell progenitor acute lymphoblastic leukemia (ALL) and the homing of these cells to the bone marrow has been well established. However the effect of modulating CXCL12/CXCR4 interactions on the growth of ALL cells in vivo has not been examined. In this study we used specific peptide and small molecule antagonists of CXCR4 to examine the importance of CXCL12/CXCR4 interactions in the development of leukemia in an in-vivo murine model of ALL. CXCR4 antagonists induced mobilization of human and murine B cell progenitor ALL cells into the peripheral blood, with a 3.8±1.9 and 6.5±3.3 fold increase in leukemic cells/ml one hour after administration of the antagonist respectively, similar to that observed for normal progenitors. Daily administration of AMD3100 commencing the day following the injection of cells and continuing for 21 days resulted in a mean reduction in peripheral blood white cell count of 50±12% and the leukemic cell count of 63±4%. There was also a significant reduction in both the total cells in the spleen of 58±1% and the leukemic cell number in this organ of 75±11%. A significant reduction in leukemic cell numbers in the bone marrow was observed in one (44% reduction) case. There was reduced infiltration of other organs including kidney, liver and skeletal muscle. This study demonstrates that disrupting the CXCL12/CXCR4 axis in B cell progenitor ALL reduces the tumor burden. Whether this is due to direct inhibitory effects on proliferation and survival, or results from disruption of the leukemic cell interactions within the bone marrow remains to be determined.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample. In addition, sequencing of the entire p53 coding region revealed no mutations in 14 of 14 xenografts (10 from patients at diagnosis and 4 at relapse). Cells harvested from the spleens of engrafted mice readily transferred the leukemia to secondary and tertiary recipients. To correlate biologic characteristics of xenografts with clinical and prognostic features of the patients, the rates at which individual leukemia samples engrafted in NOD/SCID mice were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested at relapse (r = 0.96; P =.002), but not diagnosis (r = 0.38; P =.40). In contrast, the in vivo responses of 6 xenografts to vincristine showed a direct correlation (r = 0.96; P =.002) between the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of whether the xenografts were derived from patients at diagnosis or relapse. This study supports previous findings that the NOD/SCID model of childhood ALL provides an accurate representation of the human disease and indicates that it may be of value to predict relapse and design alternative treatment strategies in a patient-specific manner.

Ultrasound-guided fine-needle aspiration cytology diagnosis of gallbladder lesions: a study of 82 cases.

Carcinoma of the gallbladder (GB) is among the five most common forms of cancers and tops the list of gastrointestinal malignancies in females of the Delhi region. Lack of specific signs and symptoms prevents early detection of GB carcinoma. However, in recent years ultrasonographically (US)-guided fine-needle aspiration (FNA) cytology has been found to be a reliable procedure for its diagnosis. The present study was carried out during a period of 5 yr (1986-1990) in 64 female and 18 male patients to find out the diagnostic utility of US-guided FNA cytology in gallbladder lesions. Ultrasonography in these 82 cases revealed a mass in the gallbladder/GB area in 74 (90.2%), a mass in the GB/pancreas in 1 (1.2%), gallstones in 32 (39.0%), and miscellaneous gallbladder lesions in 4 (4.9%). The other findings included space-occupying lesions in liver in 18 (22.0%), portal lymphadenopathy in 12 (14.6%), and infiltration in other organs in 7 (8.5%). The initial cytodiagnosis was malignancy in 48 cases, inflammatory in 12, and inadequate in 22. Following review of the smears by one of the investigators (D.K.D.), the number of malignant cases remained 48 (58.5%). There were 10 (12.2%) inflammatory and 24 (29.3%) inadequate cases. Adenocarcinoma was the most common malignancy (83.3%), followed by squamous-cell and adenosquamous carcinoma (12.5%) and small round cell tumors (4.2%). The 10 inflammatory lesions showed slight (+) to excessive (+3) neutrophilic infiltration and included one case each of xanthogranulomatous cholecystitis and a necrotizing granulomatous lesion likely to be of tuberculous etiology.

A Spectrum of Hypereosinophilic Syndromes Exemplified by Six Cats with Eosinophilic Enteritis

Of six cats with eosinophilic enteritis, two had lesions confined to the intestinal tract, and four had varied disseminated eosinophilic infiltration of other organs. The lesions in these cats are similar to those of the hypereosinophilic syndrome in man. A feline hypereosinophilic syndrome is proposed, consisting of eosinophilic enteritis, disseminated eosinophilic disease, and eosinophilic leukemia.

Gonadal infiltration in children with leukaemia and lymphoma.

In a postmortem survey of children with leukaemia and lymphoma, the overall incidence of testicular infiltration was 65% and of ovarian infiltration 66%. In acute lymphoblastic leukaemia, testicular infiltration was found in 25 of 39 cases and ovarian infiltration in 6 of 12 cases. The majority of boys with acute lymphoblastic leukaemia and testicular infiltration also had infiltration in other organs; furthermore, in most cases without testicular infiltration leukaemic infiltration was found in other organs. The findings of this survey support the view that testicular infiltration is indicative of widespread disease.

Central nervous system involvement at presentation in acute granulocytic leukemia: A prospective cytocentrifuge study

We have undertaken a perspective study of the prevelance of the central nervous disease in acute granulocytic leukemia (AGL). Thirty-nine newly diagnosed patients with AGL underwent cytocentrifuge examination of cerebral spinal fluid. Seven of the 39 patients had blast cells in their cerebral spinal fluid. All seven of these patients had acute myelomonocytic leukemia (AMML). No patients with other variants of AGL demonstrated blast cells in their cerebral spinal fluid. Other high risk factors associated with meningeal infiltration were elevated serum lysozyme levels, high peripheral white blood cell count, low age, splemomegaly and the presence of infiltration in other organs. The admission rates for patients with meningeal leukemia were lower and the survival time was shorter than in both the 32 noninvolved patients and the noninvolved patients with AMML. We believe that a lumbar puncture is indicated in all patients with newly diagnosed AMML.

An autopsy study of eye involvement in acute leukemia of childhood

The eyes of 60 children who had died of acute leukemia between 1968 and 1977 at the Children's Hospital Medical Center have been examined pathologically. An attempt has been made to relate eye findings to the state of the systemic disease at the time of death. Eight of the 60 patients had leukemic retinal infiltrates and all eight had fulminant disease with terminal leukocyte counts over 100,000 per cubic millimeter and a high percentage of "blast" cells. Twenty-six patients (43%) had leukemic infiltration of the choroid that was inapparent clinically. Choroidal involvement was not correlated with high terminal leukocyte counts but was invariably associated with widespread infiltration of other organs. Four patients had optic nerve involvement; all four had coexistent meningeal leukemia. Isolated retinal hemorrhages could not be correlated with other parameters of the leukemic process.

A study of survival in patients with stomach cancer treated by a combination of preoperative intra-arterial infusion therapy and surgery.

Since 1968, there have been 62 patients with stomach cancer seen in the First Department of Surgery of Chiba University. Treatment consisted of preoperative intra-arterial chemotherapy and surgery. The chemotherapy entailed continuous infusion for 15 to 20 hours. The survival rates were analyzed with particular emphasis on the degree of serosal invasion of the stomach. The overall survivals at the end of 3 years were 54.2% for the treated patients, and 37.1% for the controls: and at the end of 5 years, 33.3% of the treated patients were living as compared to 29.7% of the control patients. In patients without serosal invasion, the survival rates were higher for those treated than for the controls for the first 2 years. At the end of 3 years, the 39 patients treated for serosal invasion had a survival rate of 46.8% vs. 29% in the controls: and at 5 years, 32.2% of the treated patients vs. 23.7% in the controls. The survival rates for the treated patients with cancerous infiltration of other organs were about the same as those for the corresponding control patients.

Induction of lymphoid hyperplasia and lymphoma‐like disease in rabbits by herpesvirus sylvilagus

AbstractHerpesvirus sylvilagus, a recently recognized virus indigenous to cottontail rabbits, was examined for its ability to produce experimental disease in its natural host. Infection led to the establishment of a persisting low‐grade viremia in which virus was found in the cellular portion of the blood for the entire observation period. Pathologic changes seen in infected animals were related exclusively to stimulation of the lymphoid organs which varied in intensity from mild to apparently malignant. The response in all cotton tails was a generalized lymphoid hyperplasia with a corresponding lymphocytosis and the appearance of large numbers of abnormal mononuclear cells in the peripheral blood. In addition, 27% of immature cottontails (juveniles) and 10% of adult animals showed a loss of normal lymph‐node structure and massive mononuclear cell infiltration of other organs which was unrelated to destruction of parenchymal cells by the virus and which resembled, in some respects, the histologic picture seen in malignant lymphoma.