Infiltrative lymphomas

Intrinsic diseases of the small intestinal mucosa may impair mineral absorption. Such conditions as celiac sprue, dermatitis herpetiformis, infiltrative lymphomas, and occasionally inflammatory bowel disease produce diffuse mucosal damage. Protein energy malnutrition causes similar damage, and tropical enteropathy affects part of the population of developing countries living under adverse nutritional and hygienic conditions. 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

There are certain histologic subtypes of diffuse, aggressive NHL that respond less well to treatment with conventional regimens such as CHOP. Burkitt s lymphoma, lymphoblastic lymphoma, mantel cell lymphoma, and primary CNS lymphoma are examples of disease that benefit from more intensive therapy. Regimens such as hyper-CVAD, which alternate cycles of hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone with high-dose cytarabine and methotrexate, often are substituted for CHOP. Intrathecal therapy with methotrexate is indicated with documented CNS infiltration of tumor or involvement of the sinuses. The recent appreciation of the etiology of Helicobacter pylori in the etiology of peptic ulcer disease and the association between colonization and mucosal-associated lymphoma (MALT) has spurred... 

Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T-cells in B-cell non-Hodgkin lymphoma. Blood 2006 107(9) 3639-3646. 

Conditions with infiltration of bone marrow Lymphoma Leukemia Myelofibrosis Carcinoma... 

Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody used in the treatment of chronic lymphocytic leukemia and T-cell lymphoma. It targets CD52, a protein present on the surface of mature lymphocytes. Alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bron-chospasm, chills, and/or rash. Also reported were syncope, pulmonary infiltrates, cardiac arrhythmias, myocardial infarction and cardiac arrest. 

Immune dysfunction and poor tumor-specific immune responses are observed in cancer patients with enhanced Treg cell activity. Furthermore, many different types of tumors possess high frequency of Treg cells that inhibit various immune functions including T-cell proliferation, cytokine production and cytotoxic activity. Trl cells also participate in a poor anticancer response. The infiltrating lymphocytes in Hodgkin s lymphoma contain both Treg and Trl cells that suppress various immune functions. 

L Splenic marginal zone lymphoma (SMZL). These tumors involve both the white and the red pulp of the spleen. In the white pulp the neoplastic cells surround or replace the germinal centers, often with effacement of the mantle cell zone, and infiltrate the marginal zone. In the red pulp the tumor cells form nodules and sheets and infiltrate the sinuses. The neoplastic lymphocytes may circulate and involve the bone marrow (H5,19). 

A2. Nodal marginal zone lymphoma (MZL). These tumors may show a variable pattern of lymph node infiltration including parafollicular, perisinusal, nodular, and diffuse. Residual reactive follicles may show infiltration by the neoplastic cell population (S30). 

Mycosis fungoides (MF). This mature T cell lymphoma presents in the skin and is composed of small and medium-sized lymphocytes with cere-briform nuclei, which infiltrate the epidermis and dermis. Sezary syndrome is an aggressive variant of MF characterized cliniopathologically by erythroderma, lymphadenopathy, and circulating malignant cells (W9). 

Paraneoplastic autonomic neuropathy is primarily seen with SCLC [103]. Lymphoma, non-small cell lung cancer, and ovarian cancer are also associated with autonomic disturbances [104]. Autonomic dysfunction affects 23-30% of Hu antibody positive patients [36, 98] and is the predominant symptom at presentation in up to 9% of the patients [90]. The onset of symptoms is usually subacute. A prominent clinical manifestation in patients with paraneoplastic autonomic neuropathy is gastrointestinal dysmotility and intestinal pseudo-obstruction, which can occur as part of the PEM/SN syndrome or as the sole symptom of Hu antibody related PNS. Ortostatic hypotension and erectile dysfunction are other common features [37, 105, 106], Autonomic neuropathy is also commonly associated with the CRMP-5 antibody and have been detected in more than 30% of CRMP-5 antibody positive patients [30], Inflammation in autonomic ganglia and infiltration of B and T cells have been demonstrated at autopsy [107], and Hu antibodies have been shown to induce neuronal apoptosis in cultured myenteric neurons [105],... 

Infiltration of the optic nerve most often occurs from autoimmime inflammatory processes or tumor. Common infiltrative sources include sarcoidosis, SLE, leukemia, lymphoma, and primary tumors of the optic nerve. 

Lymphoma, a neoplastic malignant disorder of the lymphoid tissue, is the most common malignancy that infiltrates the optic nerve. Lymphomatous cells infiltrate the retrolaminar portion of the nerve, leading to a progressive painless loss of visual acuity, color and visual field defects, and RAPD.The disc is often swollen. 

Methotrexate Nausea and vomiting diarrhoea fever anaphylaxis hepatic necrosis Oral and gastrointestinal ulceration, perforation may occur bone marrow depression hepatic toxicity including cirrhosis renal toxicity pulmonary infiltrates and fibrosis osteoporosis conjunctivFtis alopecia depigmentation menstrual dysfunction encephalopathy infertility lymphoma teratogenesis... 

The following lesions may be hypoechoic (7.) metas-tases, (2.) liver cell carcinoma, (3.) adenomas, (4.) focal nodular hyperplasia, (5.) abscesses, (6.) haematomas, (7.) early liver infarction, (S.) foci showing reduced fatty infiltration, (9.) lymphomas, and (10.) lipomas. In individual cases, differentiation between a benign and a malignant structural defect may cause considerable difficulties. (59) (s. fig. 9.4)... 

In acute myeloid leukaemia or lymphatic leukaemia as well as in acute leukaemic episodes in non-Hodgkin lymphoma, involvement of the liver may only be detectable clinically by the presence of hepatomegaly and subicterus. Laboratory parameters usually show slightly elevated transaminase as well as bilirubin values, and distinct cholestasis is occasionally observed. (7) Acute hepatic failure can occur during the course of acute leukaemia, (l, 8,26,65) Histologically, there are massive, yet uniform blast-cell infiltrates these are found mainly within the portal fields in acute lymphatic leukaemia (about 95%) and within the sinusoids in acute myeloid leukaemia (about 75%). Involvement of the liver is of no consequence with regard to the underlying disease and its therapy. Secondary infections require systemic treatment with antibiotics and/or antimycotics. 

Hodgkin s disease and non-Hodgkin s lymphomas belong to this group. Liver involvement as a result of these diseases consists of infiltrates of lymphocytes or their precursors as well as the formation of lymphatic tissue nodes. The liver itself has no organ-specific lymphatic tissue. 

Plasmocytoma Extramedullary plasmocytic lymphoma likewise has its origin in immunoglobulin-secreting B-lymphocytes. It is also termed multiple myeloma. The condition occurs most frequently in 7 decade of life and ends fatally after 1-2 (-3) years. In the liver, there are sometimes sinusoidal and portal infiltrations of B-lym-phocytes and plasmocytic tumour cells nodular formation can also occur. Generally, however, liver involvement is found in 40% of cases. (47, 61) (s. fig. 38.12) Recently, patients with non-response or relapse after high-dose chemotherapy were treated successfully with thalidomide (starting with 200 mg daily, the dose was increased by 200 mg every two weeks until it reached 800 mg per day). (48, 56) Plasma cell leukaemia is a rare complicative variant which tends to have its own individual course. 

Centrocytic lymphomas These have their origin in lymphatic germ centre cells. Liver involvement occurs in about 50% of patients. The portal infiltrates consist of small cells with bright, irregularly shaped, indented nuclei. The portal fields are globularly distended as a result of the infiltration the limiting plates remain intact, however, and the portal bile ducts are also undamaged. 

In one patient, azathioprine-induced lymphoma with massive liver infiltration was the probable cause of fulminant hepatic failure (SEDA-21, 381). 

An 80-year-old woman with a small B cell extranodal lymphoma was initially given chlorambucil for 10 months, with complete remission for 2 years. When she developed recurrent lymph node sweUing she was given ibritumomab tiuxetan, with near-complete remission. When she developed progressive disease 14 months later, she received cyclophosphamide, vincristine, and prednisone for one cycle. She had persistent pancytopenia, and a bone marrow biopsy showed extensive infiltration by acnte myelogenons lenkemia. 

A 73-year-old man with a 5-year history of centrocytic non-Hodgkin s lymphoma presented with subcutaneous nodules in the abdominal wall at the sites where he had previously received subcutaneous injections of mistletoe (6). The nodules turned out to be infiltrations by the centrocytic lymphoma. The patient died 6 weeks later of bilateral pneumonia. The authors hypothesized that mistletoe has a growth-promoting action on lymphoma cells, mediated by high local concentrations of mterleukin-6 liberated from the skin by mistletoe lectins. 

In liver metastases, the serum alkaline phosphatase level shows a better correlation with the extent of liver involvement than those of other liver tests. To differentiate the origin of elevated alkaline phosphatase levels, tests of other liver enzymes may be performed, such as that for 5 -nucleotidase or y-glutamyltransferase. Determination of alkaline phosphatase isoenzymes may provide additional specificity. The liver isoenzyme is thermally more stable than the bone isoenzyme (see Chapter 21 for a more detailed discussion). Other malignancies, such as leuicemia, sarcoma, and lymphoma complicated with hepatic infiltration, may also show elevated ailcaline phosphatase levels. 

Intrahepatic cholestasis caused by mechanical obstruction is also common, but is rarely associated with jaundice or with visibly dilated ducts on imaging studies, although it may be associated with increased direct bilirubin. Jaundice typically occurs only with lesions that are very large, or are located near the porta hepatis, where they may obstruct both hepatic ducts. Common causes of intrahepatic obstruction include (1) tumors (particularly metastases), (2) granulomatous diseases (such as sarcoidosis and tuberculosis), and (3) infiltrative processes (such as lymphoma, leukemia, and extramedullary hematopoiesis). 

In summary Waldenstrom s macroglobulinemia seems to be a slow-growing infiltrating, widespread lymphoma whose protein production is thereby allowed to gain viscosity syndrome levels before the tumor does any direct harm. With adequate control, the prognosis is good, up to 10 years. 

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