Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis

Six patients with malignant lymphoma are described, in whom a syndrome that mimicked malignant histiocytosis clinically and pathologically developed as a terminal event. The clinical course was characterized by hepatosplenomegaly, fever, and a rapid fall in all hematologic counts. Survival from onset of this syndrome was less than six weeks. Pathologically, activation of benign histiocytes with marked erythrophagocytosis was seen throughout the reticuloendothelial system. Disseminated lymphoma was also evident but was grossly and microscopically segregated from the erythrophagocytic process. Immunologic and cytochemical studies in two cases indicated the lymphomas to be of peripheral T cell origin, whereas the phagocytic cells had markers characteristic of histiocytes. A likely mechanism for this syndrome is the production of lymphokines (macrophage-activating factors) by neoplastic T lymphocytes.     

Quantification of coronary arterial narrowing and of left ventricular myocardial scarring in healed myocardial infarction with chronic,eventually fatal,congestive cardiac failure

A qualitative and quantitative analysis is described of the amount of ventricular wall myocardial scarring and the degree and extent of coronary arterial narrowing by atherosclerotic plaques in the entire lengths of each of the four major epicardial coronary arteries in 18 necropsy patients with healed transmural myocardial infarcts, and chronic, eventually fatal, congestive heart failure. In all 18 patients, the healed infarcts involved greater than 40 per cent of the left ventricular wall, all had very dilated right and left ventricular cavities, all had hearts weighing more than 450 g (average = 587 g), all had intractable congestive heart failure for longer than three months (average = 2.3 years), and half had intraventricular mural thrombi. Of 1,012 five millimeter segments of the four major epicardial coronary arteries examined in the 18 patients (average 54 segments per patient), 298 segments (29 per cent) were 76 to 100 per cent narrowed in cross-sectional area by atherosclerotic plaques (in 16 control subjects = 6 per cent), 370 (37 per cent) were 51 to 75 per cent narrowed (controls = 35 per cent), 227 (23 per cent) were 26 to 50 per cent narrowed (controls = 43 per cent), and 117 (11 per cent) were 0 to 25 per cent narrowed (controls = 16 per cent). The amount of severe (>75 per cent) narrowing of the right, left anterior descending and left circumflex coronary arteries was similar in the 18 study patients. The left main coronary artery was not severely narrowed in any patient. The amount of severe narrowing in the distal one half of the right, left anterior descending and left circumflex coronary arteries was similar to that in the proximal halves of these three arteries. The per cent of 5 mm segments of coronary artery narrowed 76 to 100 per cent in cross-sectional area in the nine patients was similar to that in the nine patients without left ventricular aneurysm.     

Thrombocytosis, coronary thrombosis and acute myocardial infarction.

Clinical and morphologic findings are described in a 22 year old man with prolonged thromboyctosis, and coronary and splenic arterial thrombi causing myocardial and splenic infarcts. The absence of preexistent extensive coronary atherosclerosis, the presence of thrombus in more than one epicardial artery and in multiple intramural coronary arteries, the presence of arterial thrombosis in a noncoronary artery (splenic) and the absence of another apparent cause of the arterial thromboses are evidences that the intraarterial clotting in this patient was related to the severe thrombocytosis. A reveiw of the reported cases of vascular occlusion associated with thrombocytosis indicates that thrombi have infrequently been confirmed as the mechanism of the vascular occlusion. Although the frequency of vascular thrombi in patients with thrombocytosis has not been established, it is clear that vascular thrombosis can be a consequence of thrombocytosis and, as demonstrated by the present patient, that the coronary artery may be the site of the vascular occlusion, a heretofore unconfirmed event.     

Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis.

In this restrospective study we review the clinical features of patients with the sicca syndrome in the presence and absence of rheumatoid arthritis. All patients were followed at the National Institutes of Health for at least five years after the diagnosis of sicca syndrome was established. Twenty-two patients had sicca syndrome alone, and 21 patients had definite rheumatoid arthritis and the sicca syndrome. Rheumatoid arthritis tended to precede the developement of sicca syndrome. The mean age at diagnosis of sicca syndrome is the same in both groups. No significant differences in serum innumoglobulins, the third component of complement (C3), rheumatoid factor titer and salivary histopathology were found. However, the clinical features were quite distinct. Patients with sicca syndrome alone had a significantly greater frequency of recurrent parotitis, Raynaud's phenomenon, purpura, lymphadenopathy, myositis and renal involvement. The clinical characteristics of these two groups coupled with the known serologic and genetic differences suggest that sicca syndrome alone is a distinct pathologic entity.     

Lysozyme determination in parotid saliva from patients with Sjögren's syndrome

Lysozyme and total protein concentrations in parotid saliva were measured in 17 patients with primary Sjögren's syndrome, in six patients with Sjögren's syndrome secondary to hyperlipoproteinemia and in 14 age- and sex-matched healthy control subjects. Increased lysozyme concentrations were found only in patients with primary Sjögren's syndrome and correlated well with the presence of parotid gland enlargement. The total protein concentration in the saliva of patients with Sjogren's syndrome was not different from that of the control subjects. Parotid saliva lysozyme determination may be useful as an early adjunctive diagnostic test of primary Sjögren's syndrome.     

Non-Hodgkin's lymphomas in leukemic phase: Clinicopathologic correlations

A leukemic phase occurred in 30 (14 percent) of 214 patients with non-Hodgkin's lymphoma. To determine the significance of peripheral blood involvement in each type of NHL, patients were subdivided according to a modified Rappaport classification. Each histologic subtype presented a homogeneous clinical picture which differed from that seen in other histologic subtypes. Of particular note was the recognition of two distinctive cytologic and clinical subtypes within the category of nodular lymphoma, poorly differentiated lymphocytic lymphoma (NPDL). In one subtype, the predominant cells had cytologic features akin to those of lymphoblasts. In these cases, although the interval to peripheral blood involvement was variable, the median leukemic survival was only two months. In contrast in conventional NPDL the median leukemic survival was 43+ months, and peripheral blood involvement did not appear to exert an independent effect on prognosis. In diffuse large cell lymphomas the median leukemic survival was 0.5 months, with peripheral blood involvement appearing as a terminal event associated with unresponsive disease in multiple sites. The recognition of adult lymphoblastic lymphoma as a clinicopathologic entity with a high risk of leukemic conversion, 100 percent in this study, is also confirmed.     

Reversible growth hormone deficiency and delayed puberty triggered by a stressful experience in a young adult

Growth retardation and delayed puberty developed in a young man after emotional trauma at age 12 years, three months. He had an eating disorder, was profoundly malnourished for several months, and then resumed eating spontaneously. Deficient secretion of growth hormone was documented during multiple arginine-insulin tolerance tests, and gonadotropin levels were low. These hormonal deficits persisted for many years in spite of good nutrition and lack of abuse, a course inconsistent with psychosocial dwarfism or effects of malnutrition per se. Later the patient spontaneously achieved normal height and secondary sexual characteristics. Apparently, psychic trauma induced a deranged hormonal state that persisted for several years.     

Syndrome of anosmia with hypogonadotropic hypogonadism (kallmann syndrome): Clinical and laboratory studies in 23 cases

We have studied 23 patients (14 men, nine women) in 18 kindreds with anosmia and hypogonadotropic hypogonadism. Seven kindreds had more than one affected member, and included five eugonadal persons with anosmia and two eusomic women with hypogonadotropic hypogonadism. Other clinical abnormalities observed included: obesity (in nine), cryptorchidism (six), osteopenia (six), mild neurosensory hearing loss (five), gynecomastia (five), diabetes mellitus (four), cleft lip or palate or both (three), high-arched palate (two), short fourth metacarpal (two), and clinodactyly, camptodactyly, shortened frenulum of the tongue, multiple facial anomalies, right-sided aortic arch, malrotation of the gut, renal diverticulum, and mild red-green color blindness (one each).Normal secondary sex characteristics developed in all 20 patients treated on a long-term basis with chorionic gonadotropin or gonadal steroids. Responses to a single injection of gonadotropin-releasing hormone were heterogeneous. Five men had no luteinizing hormone response, five had a depressed response, and one an exaggerated response; two had no follicle-stimulating hormone response, five responses were depressed, three were normal, and one was ex-aggerated. None of seven women achieved a normal luteinizing hormone response to gonadotropin-releasing hormone; two had depressed follicle-stimulating hormone response, four responses were normal, and one was exaggerated. None of 11 patients tested responded to clomiphene. Two men fathered children. Each of two other men who underwent biopsy of the testes before and after long-term chorionic gonadotropin therapy showed mildly increased spermatogenesis. Little or no maturation beyond primordial follicles was observed in two ovarian biopsy specimens. Fifteen of 17 patients had normal basal prolactin levels and 14 of 16 had normal thyrotropin-releasing hormone-induced prolactin increase, but nine of 15 tested had a decreased or absent response of prolactin to chlorpromazine. Circulating concentrations of thyroid hormones were normal, but four of 17 patients tested had depressed TSH (thyroid-stimulating hormone) responses to thyrotropin-releasing hormone, and one man had an exaggerated response. Three of 12 patients had a depressed cortisol response to insulin-induced hypoglycemia, and two of seven patients had slightly depressed deoxycortisol responses to metyrapone. Growth hormone and vasopressin release in all 14 and all 12 patients, respectively, studied were essentially normal.Patients with anosmia and hypogonadotropic hypogonadism may have hypothalamic defect(s) responsible for the hypogonadotropism and perhaps for certain additional deficiencies of anterior pituitary function found in some. The cause of less frequent phenotypic abnormalities has not been established. In certain pedigrees, the evidence suggests that the major manifestations of the syndrome are inherited as an autosomal recessive trait.     

Isolated angiitis of the central nervous system: Prospective diagnostic and therapeutic experience

Isolated angiitis of the central nervous system is an uncommon clinicopathotogic entity characterized by vasculitis restricted to the vessels of the central nervous system without other apparent systemic vasculitis. Experience with the diagnosis, treatment, and follow-up evaluation in four patients with this disease is presented. Early manifestations of disease include severe headaches, altered mental function, and focal neurologic deficits. The pattern of progression from headaches and altered mental status to multifocal neurologic deficits is particularly suggestive of the diagnosis of vasculitis of the central nervous system. Systemic symptoms such as fever, myalgia, arthralgia, and arthritis, which occur frequently in other vasculitic syndromes, are generally not present in patients with isolated angiitis of the central nervous system. Mo single laboratory study can firmly establish or completely exclude the diagnosis; consequently, tissue diagnosis with biopsy of the brain parenchyma and leptomeninges may be required. In two patients, recurrent disease developed despite treatment with corticosteroids alone. Sustained clinical remission was induced in all four patients with a regimen of dally cyclophosphamide and alternate-day prednisone therapy. Cyclophosphamide and alternate-day prednisone therapy are considered the treatment of choice in severe, progressive, or corticosteroid-resistant isolated angiitis of the central nervous system.     

Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein

Pseudohypoparathyroidism type I is characterized by resistance (defined as a deficient urinary cAMP response) to parathyroid hormone and, in most cases, hypocalcemia and hyperphosphatemia. Many patients with pseudohypoparathyroidism type I snow a peculiar somatic phenotype termed Albright's hereditary osteodystrophy, but patients without this feature who show identical parathyroid hormone resistance have been described. Parathyroid hormone resistance in pseudohypoparathyroidism type I has been attributed to a defective parathyroid hormone receptor-adenylate cyclase complex. Recent studies have demonstrated deficient activity of the guanine nucleotide regulatory protein (G unit) of adenylate cyclase in many patients with Pseudohypoparathyroidism. Since the G unit is common to all tissues, as opposed to hormone receptors, which are tissue specific, a defective G unit should lead to resistance to multiple hormones that act by stimulating adenylate cyclase. To test this hypothesis, we studied erythrocyte G unit activity and clinical endocrine function in 29 patients with pseudohypoparathyroidism type I. Thirteen patients had deficient erythrocyte G unit activity (43 ± 9 percent of control [mean ± 1 SD]); 16 patients had normal G unit activity (92 ± 8 percent of control) (p < 0.001). Patients with deficient erythrocyte G unit activity had significantly greater (p < 0.001) basal and thyrotropin-releasing hormonestimulated thyrotropin levels than patients with normal erythrocyte G unit activity or normal control subjects (15.0 ± 6.5 and 54.3 ±22.7; 4.5 ± 2.0 and 19.5 ± 6.6; 2.0 ± 1.1 and 16.5 ± 6.7 μU/ml, respectively). In the absence of goiter or antithyroid antibody, an elevated thyrotropin level in patients with deficient erythrocyte G unit activity is consistent with thyroid resistance to thyrotropin. Furthermore, patients with deficient erythrocyte G unit activity had significantly lower (p < 0.02) integrated plasma cAMP increases to glucagon stimulation than either patients with normal erythrocyte G unit activity or normal subjects (5.1 ± 2.2 versus 8.6 ± 3.9 versus 8.6 ± 3.6 μ M × minutes), consistent with impaired hepatic cyclase responsiveness to glucagon. Clinical evidence of gonadal dysfunction was common in patients with deficient erythrocyte G unit activity, but was not observed in patients with normal erythrocyte G unit activity. These observations suggest that patients with Pseudohypoparathyroidism and deficient erythrocyte G unit activity have a disorder that is generalized to cyclase-dependent tissues, and not limited to parathyroid hormone-sensitive tissues. Moreover, it appears that patients with pseudohypoparathyroidism and normal erythrocyte G unit activity may have a defect limited to parathyroid hormone-sensitive tissues. These data support the hypothesis that a deficiency of G units is the basis for multiple hormone resistance in pseudohypoparathyroidism.     

Immunohistochemical characterization of intrathyroid lymphocytes in Graves' disease: Interstitial and intraepithelial populations

The phenotypic cell surface markers of the lymphocytes present in thyroid tissue from four patients with Graves' disease were quantitatively analyzed using the avidin-biotin immunoperoxidase technique. As control specimens, normal perinodular tissues from three patients who had benign thyroid nodules resected were also studied. In contrast to normal thyroid tissue, which contained very few T cells and no B cells, thyroid tissue of all four patients with Graves' disease contained a lymphocytic infiltrate, and this could be divided into two populations of lymphocytes. The first population was located in the follicular epithelium and expressed a cytotoxic-suppressor T cell marker (Leu2a). On the average, these cells were 4.2 times as numerous in Graves' tissues as in normal tissues (p < 0.05). Most of these cells did not express Leu1, a pan-T cell marker. The second population was found in the interstitial tissues, often within lymphoid aggregates, and 70 to 83 percent of the cells expressed Leu1. The majority of these cells expressed a helperinducer T cell marker, Leu3a; $\text{Leu3a}\text{Leu2a}$ ratios within aggregates ranged from 1.9 to 2.1. The number of B cells present was small, ranging from 5.8 to 12.1 percent of the interstitial lymphocytes. These findings are consistent with the involvement of both helperinducer and suppressor-cytotoxic T cells in a localized autoimmune reaction directed, at least in part, against the thyroid follicular epithelial cells.     

The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature.

The major cause of morbidity and mortality in patients with the hypereosinophilic syndrome is cardiac dysfunction. A review of 65 cases from the literature (historic series) revealed the following cardiovascular manifestations to be most common: dyspnea (60 per cent), signs of congestive heart failure (75 per cent), murmur of mitral regurgitation (49 per cent), cardiomegaly (37 per cent), T wave inversions on electrocardiogram (37 per cent) and pathologic findings of endocardial fibrosis, myocardial inflammation and mural thrombus formation (57 per cent). We have prospectively followed 26 patients with the hypereosinophilic syndrome for up to nine years (average follow-up prospectively was 3.3 years, retrospectively 5.7 years). Common cardiac findings in our 26 patients were dyspnea (42 per cent), chest pain (27 per cent), signs of congestive heart failure (38 per cent), murmur of mitral regurgitation (42 per cent), cardiomegaly (35 per cent) and T wave inversions (35 per cent). Thus, these patients demonstrated cardiovascular manifestations similar to those in the historic series, although the literature review showed a higher incidence of overt congestive heart failure.Of 22 patients having echocardiograms, 55 per cent demonstrated some clinical, roentgenographic or electrocardiographic evidence of cardiac involvement, but 82 per cent had echocardiographic abnormalities. This suggests that the echocardiogram is a sensitive and perhaps early indicator of cardiac involvement in this disease. Common echocardiographic findings included increased left ventricular wall thickness (68 per cent), left ventricular mass (73 per cent) and left atrial size (37 per cent). Prospective echocardiographic follow-up of 18 patients (for up to four and a half years) revealed that seven of eight untreated or inadequately treated patients had increases in left ventricular wall thickness, whereas all 10 adequately treated patients had decreases (eight of 10) or no change (two of 10) in left ventricular wall thickness. This suggests that adequate antihypereosinophilic therapy (with prednisone and/or hydroxyurea) may stabilize and, in some cases, reverse the cardiac manifestations of the hypereosinophilic syndrome.In previous studies, congestive heart failure due to eosinophilic cardiomyopathy has been reported to be very resistant to therapy. In our patients with congestive heart failure, treatment has been almost invariably effective when digitalis and diuretics were combined with adequate antihypereosinophilic therapy.     

Initial diagnosis of lipoprotein lipase deficiency in a 75-year-old man

Lipoprotein lipase deficiency, characterized by recurrent pancreatitis, profound hypertriglyceridemia, and delayed clearance of chylomicrons, is generally first diagnosed in childhood. Although patients with this condition have died during episodes of acute pancreatitis in the fourth and fifth decades, no patient older than 50 years has been previously reported. The de novo diagnosis of lipoprotein lipase deficiency in a 75-year-old man illustrates important points about this disease. This inborn error in metabolism may have a relatively benign clinical course resulting in normal life span, particularly if there is strict adherence to a low-fat diet and abstinence from alcohol. Moreover, measurement of lipoprotein lipase activity in persons with severe hypertriglyceridemia and recurrent abdominal pain, even in elderly patients, should lead to the correct diagnosis and treatment of this condition.     

Avascular necrosis in systemic lupus erythematosus. Silent symmetric osteonecroses.

The symptomatic joint disease secondary to avascular necrosis of bone (ANB) in 31 of 375 (8 per cent) patients with systemic lupus erythematosus (SLE) was characterized by polyarticular (90 per cent) and symmetric (83 per cent) involvement. Progressive deterioration requiring orthopedic intervention occurred in 11 (35 per cent) patients. No distinguishing clinical or treatment differences were found comparing patients with symptomatic ANB and selected cortico-steroid-treated, asymptomatic, control subjects with SLE. Complete roentgenographic surveys revealed symmetric, polyarticular abnormalities of subchondral and cortical bone consistent with ANB in eight of 31 (26 per cent) of the control subjects. A positive correlation was found between roentgenographic ANB and disease treatment with high doses of corticosteroids. The study suggests that ANB may be present in excess of 30 per cent of the patients with SLE and is most often subclinical, asymptomatic and nonprogressive.     

Cardiac sarcoma causing "ASH" and simulating coronary heart disease.

A patient is described in whom primary cardiac sarcoma preferentially infiltrated the ventricular septum while essentially sparing the left ventricular free wall, resulting in striking echocardiographic and morphologic asymmetry between septum and free wall (ASH). No reports have appeared previously of a patient with an intramural cardiac neoplasm demonstrated by echocardiogram. Additionally, the patient clinically had features typical of coronary heart disease, yet at necropsy the extramural coronary arteries showed insignificant (< 75 per cent) cross-sectional area luminal narrowing by atherosclerotic plaques.     

Diffuse histiocytic lymphoma in a patient treated with cyclophosphamide for Wegener's granulomatosis

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.