Gene rearrangements in malignant lymphomas.

The use of molecular methods to diagnose malignant lymphoma, while firmly established in reference centers, has not been well evaluated at the community level. A group of 57 specimens from patients with non-Hodgkin's lymphomas (NHL), lymphoid leukemias (LL), and a variety of other lymphoproliferative lesions with the Southern blot methodology have been studied by us. Molecular probes to the joining regions of the heavy (JH) and light (J kappa) immunoglobulin chains and the beta (J beta 1-2) chain of the T cell receptor genes were used. Gene rearrangements were detected in 90 percent of all NHL/LL with a 95 percent detection rate specifically for B-NHL/LL. In comparison, phenotypic analysis by immunoperoxidase stains favored a B phenotype in 75 percent of those cases, while flow cytometry assigned 63 percent of cases to a B cell lineage. Gene rearrangements were detected in four of six cases of T-NHL for a rate of 67 percent. The six other lymphoproliferative lesions included Hodgkin's disease, Castleman's disease, and a case of lymphoid hyperplasia. No rearrangements were detected in these specimens. The studies allowed development of increased confidence in the diagnosis of NHL/LL on ever smaller specimens. The availability of these studies has also helped establish a priority of handling all specimens so that the most appropriate studies can be performed to yield the most useful diagnostic information.

Malignant lymphomas associated with immunodeficiency states.

An increased incidence of malignant lymphomas is common to all types of immunodeficient patients whether they be of the natural or constitutionally occurring type, acquired as in acquired immunodeficiency syndrome (AIDS) or of iatrogenic origin as in organ transplantation. Although there is some degree of heterogeneity, the most characteristic feature of these immunodeficient states is alteration of T-cell cytotoxic function. The malignant lymphomas show a variety of relatively common features, notably: rapid onset following the appearance of the immunodeficient state, a high degree of clinical aggressiveness, and a tendency to present in extranodal sites, particularly the central nervous system (CNS) and gastrointestinal tract. The tumors are almost invariably of B-lymphocytic cell origin and while the histologic classifications reflect some diversity, the vast majority of tumors are described as Burkitt-like or diffuse large cell type. There appears to be a high degree of correlation with a preceding fulminant Epstein-Barr virus (EBV) infection resulting in marked B-cell lymphoproliferation in the absence of effective T-cell control. Initially, the B-cell proliferation is clearly polyclonal and reactive in nature, although as time evolves, there appears to be selection of oligoclonal and even monoclonal cell populations. Such cells are latently infected with EBV and may express EBV nuclear protein two and latent membrane protein, which are characteristically seen in proliferating B-lymphocytes in response to growth transformation by EBV. While desoxyribonucleic acid (DNA) probes may continue to demonstrate multiple lymphoid clonal populations, it is hypothesized that the hyperproliferative state favors genetic alterations which select out a single malignant clone. This transformed clone is evidenced by expression of a translocated, activated c-myc oncogene and decreased evidence of EBV nuclear protein two and latent membrane protein, that is, characteristics of Burkitt's lymphoma. Other large cell malignant lymphoma phenotypes may show similar findings. While most studies have continued to suggest that EBV plays a key role in the development of non-Hodgkin's lymphoma (NHL) of AIDS patients, some recent studies have suggested a less dominant role. Therefore, further exploration of the world of molecular biology will be needed to demonstrate whether other factors, namely additional viruses and/or oncogenes play a similar or significant role in the lymphomas of immunodeficient patients.

Control of oral anticoagulant therapy.

In an effort better to standardize the control of oral anticoagulant therapy, it has recently been recommended that the prothrombin time be reported in the form of an International Normalized Ratio (INR) based upon calibration of the locally employed thromboplastin with an International Reference Preparation. It has been demonstrated in our laboratory that the INR does minimize the differences in results which ensue from variations in the source of thromboplastin and instrumentation and should hopefully allow for better interlaboratory comparisons in the future. Recent studies have also suggested that many American patients tend to be over anticoagulated and at greater risk for hemorrhage. Based upon those findings, over 40 percent of our specimens were above the currently recommended levels.

Hepatic manifestations of lymphomas.

The various hepatic manifestations of malignant lymphomas are discussed as well as the methods employed to detect hepatic involvement in those diseases. Hepatomegaly is infrequent in early Hodgkin's disease and, when present, may represent a nonspecific reactive phenomenon. Hepatomegaly is more common in non-Hodgkin's lymphomas and various leukemias and usually represents neoplastic involvement of that organ. Radiographic procedures and liver function studies are unreliable in detecting liver involvement although correlation of the various data increases diagnostic accuracy. Morphological manifestations of these diseases are discussed as well as those methods which are best suited for diagnosis.

The preleukemic syndrome.

While the preleukemic syndrome (PLS) is not a homogeneous entity, its spectrum of clinical and laboratory findings has been sufficiently characterized to allow increasing certainty in its recognition. Approximately 25 percent of these patients can be expected to develop overt acute nonlymphocytic leukemia (ANLL) within an average of two to three years, and another 40 percent will die of non-leukemic complications usually related to their cytopenias within a similar time period. The remaining patients may be stable and survive for prolonged periods. Accumulating evidence indicates that in the PLS, a stem cell neoplastic clonal proliferation has already been established and may frequently be demonstrated by cytogenic analysis or culture of marrow hematopoietic cells.

Transient reticulocytopenia in viral illness.

Infection resulting in transient reticulocytopenia and anemia, the so called "aplastic crisis," has frequently been documented in patients with congenital hemolytic anemia. However, this association with hematologically normal patients has been less well recognized. Its occasional severity is illustrated by this report of two cases of marked reticulocytopenic anemia in association with probable viral infections. These were previously health children whose anemias could be explained only by a temporary interruption of erythropoiesis. These patients recovered spontaneously and were in good health one year later. A subsequent separate survey of leukopenic patients with a wide variety of viral infections demonstrated significant reticulocytopenia in seven of 35 patient (20 percent). It is concluded that in addition to the more widely appreciated neutropenia and thrombocytopenia of viral infections, reticulocytopenia is a common manifestation of many viral infections and may occasionally result in profound anemia.

Heterotopic pharyngeal brain.

We report a case of heterotopic brain tissue in the oropharynx without connection to the CNS. We attempt to differentiate this developmental anomaly from encephaloceles and nasal gliomas, in which a communication with the CNS may lead to the development of postoperative meningitis.

Acanthocytosis--biochemical and physiological considerations.

Acanthocytosis represents an unusually pathological variant of red cell morphology which is encountered in a diverse group of inherited and acquired disease states. While the morphological features are similar in all instances, the biochemical lesions frequently differ. Most demonstrable abnormalities involve lipids although those acanthocytes associated with the McLeod phenotype are probably due to an alteration in a membrane protein. Acanthocytes, regardless of their etiology, usually have a decreased survival in the circulation owing to splenic sequestration and destruction.

Atypical retinitis pigmentosa in familial hypobetalipoproteinemia.

Of three patients with familial hypobetalipoproteinemia, a 42-yeear-old white woman, who was homozygous for this autosomal dominantly inherited disease, had no detectable serum betalipoprotein and had a marked retinal pigmentary degeneration characterized by ring scotomas by Goldmann perimetry, extinguished electroretinographic responses, delayed responses and elevated thresholds during dark adaptometry, and abnoramal cone thresholds. A 4-year-old daughter and a 28-year-old niece of the first patient, who wer heterozygous, had reduced but detectable levels of serum betalipoprotein and no significant retinal pigmentary degeneration. Unlike patients with autosomal recessively inherited abetalipoproteinemia (the Bassen-Kornzweig syndrome), none of our patients had significant neurologic of cardiac defects. Although the level of serum betalipoprotein might be correlated with retinal pigmentary degeneration in familial hypobetalipoproteinemia and abetalipoproteinemia, it appears that neurologic and cardiac defects are dependent on other factors.

The genetic relationship of abetalipoproteinemia and hypobetalipoproteinemia: a report of the occurence of both diseases within the same family.

A new case of abetalipoproteinemia (ABL) is reported after its recognition during an acquired hemorrhagic disthesis at parturition in a 37-year-old female. The new born infant of that delivery and 4 other first-degree relatives were subsequently studied and found to have hypobetalipoproteinemia (HBL). ABL and HBL, while sharing many clinical and biochemical similarities have, but rarely, been demonstrated within the same kindred and have, therefore, been regarded as different genetic mutations. Analysis of the data in the present and two other reported families indicates that ABL can result from the homozygous inheritance of the same gene which, when present in the heterozygous state, results in HBL't is concluded, therefore, that these cases of ABL have apparently been inherited via a different genetic mutation than most previously reported cases of ABL,and is likely the same gene involved in HBL. The clinical presentation of this form of ABL, that is, familial homozygous hypobetalipoproteinemia, is compared to that of the classical form of ABL.