Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine.

Three patients with pancreatic carcinoma treated with gemcitabine for 1 year developed clinical and laboratory findings compatible with an indolent form of the hemolytic-uremic syndrome. Renal biopsy specimens in two of these patients showed the characteristic features of thrombotic microangiopathy, and a skin biopsy specimen from the third patient, who presented with livedo reticularis, showed intravascular fibrin deposition. Thrombotic microangiopathy may represent a toxic effect of long-term gemcitabine therapy.

Cytomegalovirus infection of renal allografts. Detection by polymerase chain reaction.

Early laboratory diagnosis of acute cytomegalovirus infection in renal transplant recipients is desirable but often difficult. The polymerase chain reaction (PCR) technique for detecting CMV DNA, although it promises a high sensitivity, risks the possibility of detecting latent CMV infection and leading to false-positive results. To address this issue and the feasibility of applying PCR to renal biopsy specimens, we analyzed 37 renal allografts by PCR. Formalin-fixed or Bouin-fixed paraffin-embedded materials were employed, and primers from the LA (late-antigen) region of CMV were used. Amplified products were detected by gel electrophoresis and ethidium bromide staining, followed by Southern blot analysis. Of 21 nephrectomy samples, three showed CMV-specific amplified products by PCR, but CMV inclusion bodies were detected histologically in only one of the three. Of 16 renal biopsies, three specimens were positive by PCR, with rare viral inclusions histologically identified in only one. All PCR-positive patients had clinically significant CMV disease as evidenced by positive CMV culture and/or seroconversion. In contrast, all CMV-seropositive patients without active viral disease had PCR-negative allografts. We conclude that PCR positivity in the renal allograft strongly correlates with active CMV disease but not latent infection. For the diagnosis of active CMV disease in patients with a renal allograft, PCR provides a means that is more sensitive and objective than histologic examination, more specific than serology, and faster than viral culture.

Immunohistochemistry and gene rearrangement studies in the diagnosis of malignant lymphomas: a comparison of 152 cases.

One hundred fifty-two cases (155 specimens) of lymphoproliferative disorders were studied by immunohistochemistry and gene rearrangement analysis. Ninety-five of 96 B-cell lymphomas (99%) showed genotypic B-cell monoclonality. Of these, five cases had rearranged T-cell receptor (TCR) beta chain gene in addition to immunoglobulin heavy chain (IgH) and kappa light chain (Ig-K), one case had rearranged IgH and TCR-gamma chain but not Ig-K or TCR-beta, and two cases had only Ig-K rearrangement. One exceptional case in the B-cell lymphoma group had unrearranged, germline genotypes. In contrast, only 10 of 19 (53%) phenotypic T-cell lymphomas had rearranged TCR-beta, eight with concurrent TCR-gamma rearrangement. Of the remaining nine cases, six had germline configuration, two had rearranged Ig-K only, and one had both IgH and Ig-K rearrangement. This last case was reclassified as T-cell predominant, B-cell lymphoma. Thirteen of 16 cases of Hodgkin's disease had germline configuration; three cases had rearranged IgH and Ig-K, of which two were lymphocyte predominant with light chain monoclonality and one was a recurrence. Among 21 reactive lesions, 17 had germline configuration and four had rearranged IgH and Ig-K genes. Of these four cases, two were orbital lesions, one was a partially involved lymph node, and one developed a nodular lymphoma 9 months later. Our results indicate that almost all B-cell lymphomas have IgH and/or Ig-K rearrangement. In contrast, peripheral T-cell lymphomas have greater genotypic heterogeneity, and germline patterns for TCR genes are not uncommon. Reactive lesions and Hodgkin's disease tend to retain germline configuration, and any exception is often associated with an unusual clinical setting and/or histology. Genotypic analysis is thus most indicated in B-cell lymphomas with equivocal immunohistochemistry findings, T-cell lymphomas, and atypical cases of Hodgkin's disease and reactive lesions.

Central nervous system lymphoma in the acquired immunodeficiency syndrome.

Primary central nervous system (CNS) lymphomas were studied in fifteen autopsied patients with the acquired immunodeficiency syndrome (AIDS). Using the working formulation for non-Hodgkin's lymphomas, the tumors were classified as large cell (7 patients), mixed large and small cell (6 patients), small cleaved cell (1 patient), and unclassifiable (1 patient). The mixed lymphomas displayed unusual features characterized by a high mitotic rate and the presence of numerous medium-sized cells (5 to 10 mus), not classifiable using the working formulation. Focal T cell and lymphoplasmacytoid B cell infiltrates accompanied lymphoma cells at the periphery of and remote from solid tumor masses in 9 cases. Immunohistochemical analysis of the lymphomas suggested B cell neoplasms. All of these patients had concurrent CNS and systemic cytomegalovirus (CMV) infections. The CNS infections were of both viral (CMV, human immunodeficiency virus (HIV), varicella zoster virus (VZV), progressive multifocal leukoencephalopathy (PML) and non-viral (toxoplasmosis, candidiasis) etiology. In the general AIDS population at our institution, the autopsy incidence of CNS infections and systemic CMV was 63% and 60%, respectively. In contrast, the incidence for both these entities was 0% in otherwise healthy, non-AIDS patients with CNS lymphoma supports the hypothesis that viral infection plays a role in the pathogenesis of CNS lymphoma in the immunocompromised. Polyclonal lymphoplasmacytoid B and T cell infiltrates accompanying lymphoma may produce diagnostic difficulties on surgical biopsy. As these infiltrates were a frequent feature in this study, we caution that their recognition does not argue against the presence of CNS lymphoma.

Lymph node biopsy in patients with human immunodeficiency virus infections.

Twenty-one male homosexuals were followed up by repeated lymph node biopsy for a mean (+/- SEM) follow-up of 99 +/- 18 weeks. Four histologic patterns were seen on biopsy: explosive follicular hyperplasia (EFH), follicular involution (FI), a mixed pattern of EFH with FI in the same node, and lymphocyte depletion. Patients with FI and lymphocyte depletion had mean survival times that were significantly less than those for the subjects with EFH. The percentage of lymph node follicles with suppressor cell clusters (T8) in EFH lymph nodes was significantly higher (43% vs 8%) than in nodes from patients without risk for human immunodeficiency virus infection. Helper/suppressor T-cell ratios in control nodes were 1.6; in EFH nodes, 0.97; and in FI nodes, 0.88. A remarkable 33% of patients in this lymphadenopathy group ultimately developed large-cell (B-cell) lymphoma, suggesting that the follicular stimulation noted histologically played a role in the development of this neoplasm. These data show that there is a progressive destruction of lymph node follicles that correlates with the progression of the disease and that lymph node histologic features may provide important prognostic information.

Cytomegalovirus infection of the alimentary canal: radiologic findings with pathologic correlation.

A spectrum of radiologic findings in cytomegalovirus (CMV) infection of the alimentary canal seen in 14 patients and correlated with pathologic examinations is described. Twelve patients had acquired immunodeficiency syndrome and two had no identified immunosuppression. Autopsies were performed on 12. Diffuse CMV colitis was present in eight patients, enteritis in seven, esophagitis in four, gastritis in two, cholangitis in one, and acute pancreatitis in one. Of 11 patients with enteritis and/or colitis seven had significant lower gastrointestinal bleeding and five died as a result of it. Radiologic findings in the gastrointestinal tract included superficial or deep mucosal ulcerations, perforation or fistula formation, luminal narrowing, rigidity and thickening of the intestinal wall, and inflammatory infiltration of the mesentery. These were seen on barium examinations and computed tomographic (CT) scans. Findings of pancreatitis were seen on CT scans in one patient. In another, a cholangiogram showed abnormal bile ducts caused by CMV cholangitis. The radiologist should be aware of the diverse manifestations of the disease and its likely occurrence in immunosuppressed individuals.

Chromosome abnormalities in AIDS-associated lymphadenopathy.

Cytogenetic studies were performed on direct and 24-hour culture preparations of eight lymph node biopsies from seven patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC)-associated lymphadenopathy in whom histological evidence of lymphoma was not detected. Three of these seven had chromosomal abnormalities, including chromosome instability in one and clonal chromosomal abnormalities in two; one of the latter was a t(8;14)(q24;q32). The remaining five showed normal karyotypes. Epstein-Barr virus (EBV) titers were elevated in all three patients that exhibited chromosome abnormalities, two of whom later developed malignant lymphoma. A control group of five patients with reactive lymphadenopathy not associated with AIDS failed to reveal chromosomal aberrations, but elevated EBV titers were present in two. These data are consistent with current views on the role of EBV and chromosome change in the development of lymphoma in immunodeficient states and suggest that karyotypically abnormal AIDS-related lymphadenopathy represents a prelymphomatous proliferation.

Malignant lymphomas and the acquired immunodeficiency syndrome. Evaluation of 30 cases using a working formulation.

Malignant lymphomas occurring in 29 homosexual men and one thalassemic woman with the acquired immunodeficiency syndrome or the acquired immunodeficiency syndrome-related complex are reported using a working formulation for non-Hodgkin's lymphomas (NHLs). The patients' ages ranged from 25 to 59 years, with an average age of 42 years. Ninety percent of the cases were extranodal; 67% were exclusively extranodal. One case of Hodgkin's disease was encountered. All NHLs were of the diffuse types in both the intermediate- and high-grade categories, with the largest single group (49%) being of the diffuse, large, follicular-center-cell types. The NHLs in this series were classifiable as B-cell neoplasms and were aggressive as evidenced by markedly reduced median survivals. The morphological diagnosis as defined in the working formulation, especially for the intermediate-grade lesions, offered little significant prognostic information.

Biliary tract obstruction in the acquired immunodeficiency syndrome.

Three patients with the acquired immunodeficiency syndrome had biliary obstruction resulting from benign strictures of the biliary tract. Stenosis of the distal common bile duct with differing degrees of irregularity of the smaller intrahepatic and extrahepatic ducts was seen in association with either cryptosporidial or cytomegaloviral infection of the biliary tree. We review cytomegaloviral and cryptosporidial infections of the biliary system, as well as possible relationships with idiopathic primary sclerosing cholangitis. Stenotic biliary tract disease appears to be yet another complication of the acquired immunodeficiency syndrome.

Diagnostic pathology in the acquired immunodeficiency syndrome. Surgical pathology and cytology experience with 67 patients.

We report the pathologic findings in specimens submitted for histologic and cytologic evaluation from 67 patients with the acquired immunodeficiency syndrome. A wide variety of opportunistic pathogens were identified in 41 patients. Mycobacterium avium-intracellulare evoked only a mild host response: granulomas, if present, were poorly formed. Biopsy specimens showing cytomegalovirus gastroenteritis required sections at multiple levels to demonstrate inclusions. Combined histologic and cytologic evaluation can increase the diagnostic yield in pulmonary and esophageal infections. Kaposi's sarcoma was found in biopsy specimens from 29 patients. Early lesions were often extremely subtle, yet distinct from, benign vascular proliferations in involuted lymph nodes. Malignant lymphoma was diagnosed in ten homosexual men who were suspected of having the acquired immunodeficiency syndrome. The lymphomas were characterized by B-cell origin, a diffuse pattern, frequent extranodal presentations, and an aggressive clinical course with prominent central nervous system involvement.

Immature teratoma of the ovary with predominant malignant retinal anlage component. A parthenogenically derived tumor.

An immature teratoma with predominant malignant retinal anlage component occurred in the ovary of a 17-year-old woman. Karyotype analysis from Q-banded preparations revealed that the tumor was parthenogenically derived and exhibited chromosome instability and aneuploidy. On light-microscopical examination, the malignant elements resembled retinal anlage. Ultrastructurally, large, polygonal, pigmented cells had features of ependymal epithelium: a continuous, well-developed basal lamina; microvilli; parallel arrays of rough endoplasmic reticulum; and very large, densely pigmented melanosomes. Adjacent cells identified by light microscopy as immature neuroglia contained glial fibrillary acidic protein by immunohistochemical staining. The presence of neuroglia, not a feature of tumors of neural crest origin, and the ependymal characteristics of the pigmented cells indicate that the neoplasm was most likely of neural groove derivation.

Aggressive plasma cell myeloma. A terminal phase.

Seven patients with plasma cell myeloma experienced an aggressive, terminal phase. This phase is characterized by rapidly enlarging soft-tissue masses with tumor morphologic characteristics similar to a poorly differentiated or large-cell (histiocytic) lymphoma, with rapid death, and often with fever, pancytopenia, decreasing levels of myeloma protein, and younger age. Median survival from the onset of the phase was four months. There was no response to single-agent or combination chemotherapy. In view of the extremely poor prognosis and lack of response to conventional treatment, patients experiencing this characteristic terminal phase should be considered candidates for innovative therapy.

Proteinuria during long-term captopril therapy.

Proteinuria developed in six of 81 hypertensive patients given captopril for at least four months (protein excretion, greater than 200 mg/24 hr). Two had previously elevated protein excretion. In all patients the increased protein excretion occurred by the fourth month of treatment. It subsided in four after two to nine months, despite continued therapy. In two of the four, proteinuria cleared completely within seven months after onset, while in the other two it subsided to the range of 600 mg/24 hr. However, in the remaining two patients proteinuria persisted during captopril therapy and was associated with hypoalbuminemia and hypercholesterolemia. Renal biopsy specimens showed mild membranous nephropathy in two patients, one of whom had a remittance of proteinuria during continued captopril treatment.

Mesangial electron-dense deposits in membranous nephropathy.

In the absence of lupus, mesangial electron-dense deposits in membranous nephropathy are thought to be uncommon. In this study 18 renal biopsies of 16 cases seen over a 2-year period were evaluated by light and electron microscopy and immunofluorescence, directing particular attention to the mesangium. Lupus had been excluded in every instance by the usual serologic tests. In seven of the 18 biopsies, mesangial electron-dense deposits were found. Clinically, almost all of these patients were characterized by atypical features: five patients had underlying diseases which have been associated with membranous nephropathy (renal vein thrombosis, epidermoid carcinoma of the lung, SH-antigenemia, rheumatic heart disease and penicillamine therapy); there was one instance of spontaneous remission and another patient who progressed to terminal renal failure in less than 2 years. The results suggest that the presence of mesangial deposits in membranous nephropathy may be more common than has previously been suspected. This finding is not necessarily associated with systemic lupus erythematosus and may indicate an unusual or atypical form of membranous nephropathy.

Delayed hyperacute rejection in recipients of kidney transplants from HLA identical sibling donors.

Delayed hyperacute rejection, with its characteristic clinical course and histopathologic findings, occurred within one month after transplantation in five recipients of kidney transplants from HLA-A, B and D identical sibling donors. In all cases, unidirectional mixed lymphocyte cultures and immunologic studies to detect cytotoxic antibodies in the recipients against their respective donors, before kidney transplantation and after transplant nephrectomy, were unresponsive or negative. Onset of delayed hyperacute rejection was preceded by bacteremia in two of these patients. Two of these received second kidney transplants, three to six months later, from HLA-A, B and D identical sibling donors again. Although both have had an episode of acute rejection in the early postoperative period, the grafts have maintained excellent function for 21 and 25 months, respectively. Irreversible forms of transplant rejection, such as delayed hyperacute rejection, do occur even in recipients of kidney transplants from HLA-A, B and D identical sibling pairs, indicating that genetic determinants other than HLA-A, B and D loci, and perhaps other nongenetic immune mechanisms, play an important role in the ultimate results of kidney transplantation.

Hemangioendothelial sarcoma of penis.

Hemangioendothelial sarcoma of the penis in a 44-year-old man was treated by preoperative radiation, penectomy, and chemotherapy. The patient was free of evident disease 2 years later. Electronmicroscopy showed differentiated vascular structures at the periphery of the lesion and anaplastic cells throughout the remainder of the tumor.

Immunoblastic lymphadenopathy and adenocarcinoma of the pancreas: a case report.

Immunoblastic lymphadenopathy developed 5 months before the clinical manifestation of an anaplastic adenocarcinoma of the pancreas in a 53-year-old male. The possible association and significance of this relationship, which has not been hitherto reported, is discussed.

Renal transplantation between HLA identical siblings. Comparison with transplants from HLA semi-identical related donors.

We compared 26 HLA-A, B identical sibling kidney-transplant recipients followed for one to 10 years, with 104 HLA-A, B semi-identical kidney recipients from living, related donors to determine clinical differences. Graft-survival rates were significantly better in the HLA identical group at two years (85 per cent identical versus 53 per cent in semi-identical, P less than 0.005); patient-survival rates were high for both (96 per cent in identical and 87 per cent in semi-identical at two years, P less than 0.005). The incidence of complications was similar in HLA identical and semi-identical recipients. Nine of the 26 grafts in HLA identical recipients failed one week to eight years after transplantation. Rejection caused most of the graft failures. Recipients of HLA identical-sibling kidney transplants have a high patient and graft survival, but they also encounter many complications. Immunologic rejection occurs, even with negative mixed lymphocyte culture, suggesting the importance of donor determinants other than the HLAA, B and D other than the HLA-A, B and D.