Arnold B. Gelb

Helicobacter pylori infection and gastric lymphoma

BACKGROUND Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. We examined whether this infection is also a risk factor for primary gastric non-Hodgkins lymphoma. METHODS This nested case-control study involved two large cohorts (230,593 participants). Serum had been collected from cohort members and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkins lymphoma were identified, and each was matched to four controls according to cohort, age, sex, and date of serum collection. For comparison, 31 patients with nongastric non-Hodgkins lymphoma from one of the cohorts were evaluated, each of whom had been previously matched to 2 controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples from all subjects were tested for H. pylori IgG by an enzyme-linked immunosorbent assay. RESULTS Thirty-three cases of gastric non-Hodgkins lymphoma occurred a median of 14 years after serum collection. Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9). The results were similar in both cohorts. Among the 31 patients with nongastric lymphoma, a median of six years had elapsed between serum collection and the development of disease. No association was found between nongastric non-Hodgkins lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95 percent confidence interval, 0.5 to 3.0). CONCLUSIONS Non-Hodgkins lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.

Renal cell carcinoma. Prognostic significance of morphologic parameters in 121 cases

Morphologic parameters were correlated with survival in 121 renal cortical neoplasms including 116 carcinomas and five oncocytomas. An increasing nuclear grade was generally correlated with a significant decrease in disease‐free survival although no statistical difference was found between nuclear Grade 1 and 2 tumors. Similarly, a higher stage at diagnosis predicted a shorter disease‐free survival. Renal vein invasion adversely affected prognosis only for high nuclear grade carcinomas. Papillary and spindled carcinomas, independent of nuclear grade, were associated with a significant decrease in disease‐free survival compared to tumors with a solid pattern. Patients with large neoplasms (greater than 10 cm) had a significantly worse disease‐free survival than patients with tumors 10 cm or less. The prognostic significance of tumor cell type is less clear. Patients with oncocytomas had the best disease‐free survival compared with patients with tumors of other cell types. However, the difference in survival was not statistically significant for low‐grade tumors, suggesting that nuclear grade rather than cell type may be the more important determinant.

Solitary fibrous tumor involving the renal capsule.

Solitary fibrous tumors are spindle-cell neoplasms that originally were described in the pleura but that can occur in a large variety of sites. We report a well-circumscribed tumor, apparently involving the renal capsule, clinically thought to be a renal-cell carcinoma or oncocytoma. It was composed of bland spindle-shaped cells with a patchy lymphoplasmacytic infiltrate, suggesting sarcomatoid renal-cell carcinoma, inflammatory myofibroblastic tumor, or solitary fibrous tumor; however, immunohistochemical stains were negative for keratin, alpha-smooth-muscle actin, and desmin but strongly positive for CD34. Ultrastructural examination revealed fibroblast-like cells without myofibroblastic or epithelial differentiation. The combined findings favor a diagnosis of a solitary fibrous tumor involving the renal capsule. To our knowledge, this lesion has not been reported in this location.

Transitional Cell Carcinoma of the Prostate in Patients Undergoing Radical Cystoprostatectomy

To assess the impact of prostatic involvement with transitional cell carcinoma we reviewed the clinical outcome of 49 patients with transitional cell carcinoma of the prostate. In addition, 115 step-sectioned cystoprostatectomy specimens removed for bladder transitional cell carcinoma were studied to determine the true incidence of secondary prostatic involvement by transitional cell carcinoma. Specimens from 300 prostates removed for prostatic adenocarcinoma also were reviewed to investigate the presence of incidental transitional cell carcinoma arising within the prostate. Transitional cell carcinoma was found in 29% of the step-sectioned specimens and in none of the radical prostatectomy specimens. The presence of prostatic invasion either into the stroma or involving prostatic ducts and acini only had no adverse effect on outcome. Lymph node status and bladder stage, and not prostatic invasion were the determining factors of survival. The presence of seminal vesicle involvement or prostatic stromal invasion appeared to predict for lymph node involvement. With a mean followup of more than 3 years 75% of our patients who had negative lymph nodes and low stage bladder lesions are alive without evidence of disease. In our series prostatic involvement by transitional cell carcinoma did not impact on survival when patients were treated aggressively with radical cystoprostatectomy.

Numbers of host "helper" T cells and proliferating cells predict survival in diffuse small-cell lymphomas.

Diffuse small-cell lymphomas of B-lineage comprise a group of immunophenotypically related lymphoid malignancies that display variable clinical aggressiveness. We compared a variety of clinical, pathologic, and immunologic characteristics of 64 B-lineage diffuse small-cell lymphomas to patient survival in an effort to define prognostically relevant subtypes of these neoplasms. Neither clinical parameters nor histological subclassification correlated with patient outcome. In contrast, three immunologic features of these lymphomas showed a statistically significant relationship with actuarial survival. Neoplasms that manifested greater than or equal to 25% Ki-67+ cells (proliferation-associated antigen), less than 25% Leu 4+ cells (pan-T antigen), or less than 15% Leu 3+ cells (helper/inducer T-subset antigen) were associated with significantly decreased patient survival as compared to neoplasms with the reverse phenotype (P = .02, P = .003, P = .0005, respectively). Leu 3 findings were of particular importance in initial biopsies (P = .0007), while the Ki-67 findings were significant regardless of time of biopsy (P = .01 for biopsies at diagnosis and P = .004 for other biopsies). These data indicate that immunologic analysis can demonstrate subsets of diffuse small-cell lymphoma with different biologic potential, and suggest that such analysis be included in the routine work-up of patients with this type of neoplasm.

Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia

We describe the first case of an Epstein-Barr virus (EBV)-associated natural killer-large granular lymphocyte (NK-LGL) leukemia in the United States to the best of our knowledge. A 29-year-old woman of Japanese descent developed EBV infection after a blood transfusion as indicated by a rise in serum antibody titers. Peripheral blood and bone marrow aspirate smears demonstrated increased LGLs. Flow cytometry showed that these cells expressed NK-associated surface antigens. Cytogenetic analysis of the bone marrow aspirate showed two distinct but related clones with multiple copies of a modified 7 marker chromosome. Death followed colonic perforation. Findings at necropsy included bone marrow lymphocytosis and erythrophagocytosis, a mononucleosis-like lymphadenitis, atypical hepatitis with a mixed, predominantly T-cell infiltrate, interstitial pneumonitis, and multiorgan system vasculitis with perforation of the transverse colon. Epstein-Barr virus transcripts were identified in lymphocytes infiltrating liver and peripheral nerve by in situ hybridization. In addition, Southern blot analyses showed monoclonal bands superimposed on oligoclonal ladders of EBV termini in liver and lymph node. The identical episomal form of EBV was found in the bone marrow, lymph node, and liver. No immunoglobulin (Ig), T-cell receptor beta, or T-cell receptor gamma chain gene rearrangements were identified. These studies support the hypothesis that the LGL population was a neoplastic EBV-related clonal proliferation of NK cells.

Low-grade renal cell carcinoma: A clinicopathologic study of 53 cases

Fifty-three low-grade renal cell carcinomas and oncocytomas were reviewed to assess the prognostic significance of nuclear grade (grade 1 versus grade 2), character of cell cytoplasm, size, and stage. Twelve of 46 patients (27%) with follow-up died of disease. Stage 4 disease (most often, extensive local spread) best predicted decreased survival. The survival of patients with stage 1, 2, and 3 tumors was similar; and renal vein invasion was not an adverse prognostic indicator. Size also appeared to predict patient survival; tumors greater than 10 cm metastasized at a higher rate than neoplasms 5 cm or less. We were unable to demonstrate statistically significant differences in survival between individuals with grade 1 and 2 neoplasms, nor were we able to demonstrate a statistically significant difference in survival on the basis of the character of the cell cytoplasm. However, there was a trend toward better survival for patients with granular cell carcinomas and oncocytomas as opposed to neoplasms with clear or mixed cell cytoplasm. Although the number of patients with granular cell carcinomas and oncocytomas is small, the data suggest that the distinction between low-grade granular cell carcinomas and oncocytomas adds little prognostic information.

Coexistence of nodular lymphocyte predominance Hodgkin's disease and Hodgkin's disease of the usual type.

Recent literature suggests that usual Hodgkins disease (nodular sclerosing and mixed cellularity types or UHD) and nodular lymphocyte predominance Hodgkins disease (NLPHD) may be distinct clinical and pathologic entities. Thus, coexistence of NLPHD and UHD in the same patient is expected to be rare. We undertook a review of cases accessioned as NLPHD and UHD in the Laboratory of Surgical Pathology at Stanford University Hospital between January 1980 and May 1992 and found five patients with UHD that predated, followed, or coexisted with lesions histologically typical of NLPHD. All of the patients were male with ages ranging from 10 to 30 years at presentation (median, 22 years; mean, 22.2 years). The sites initially involved by disease were primarily peripheral lymph nodes in the region of the head and neck: cervical (three), supraclavicular (one), submandibular (one). One patient presented with mixedcellularity Hodgkins disease (MCHD), two with nodular sclerosis Hodgkins disease including the cellular phase, one with NLPHD, and the remaining patient presented with a composite malignancy comprising MCHD and NLPHD. Development of the second lymphoma was associated with a somewhat more variable distribution of nodal involvement. The morphologic features in each biopsy specimen resembled either typical NLPHD or UHD, except for one case in which cells with features of both Reed-Sternberg cells and lymphocytic and histiocytes cells were identified. However, the immunophenotypic profiles obtained with a panel of monoclonal antibodies remained distinct for all cases studied. None of the cases showed reactivity with antibodies against the Epstein- Barr-virus latent membrane protein. Thus, NLPHD and UHD maintain a distinct phenotype, even when occurring in the same patient. A second conclusion is that the utility of Leu-7 (CD57) reactivity in distinguishing NLPHD applies to problematic as well as classic cases. Finally, Epstein-Barr virus is not implicated in NLPHD cases associated with UHD.

Renal insufficiency secondary to 2,8-dihydroxyadenine urolithiasis☆

A 48-year-old man with a history of recurrent urolithiasis and chronic renal failure underwent a nephrectomy for a renal mass. At surgery the mass proved to be a calculus impacted in a dilated calyx. Gross examination of the kidney revealed chalky white deposits in the deep medulla and papillary tips. Histologic examination revealed chronic interstitial nephritis with brown spicules within some tubular epithelial cells and larger deposits of brown crystals within tubular lumina, the interstitium of the medulla, and papillary tips. Polarization microscopy revealed individual crystals scattered throughout the renal parenchyma. Although the arrangement of the crystals was reminiscent of uric acid, and, in fact, a clinical diagnosis of gouty nephropathy was made, x-ray diffraction analysis demonstrated crystals of 2,8-dihydroxyadenine. Enzymatic studies confirmed the complete absence of adenine phosphoribosyltransferase activity in erythrocyte lysates.

The Molecular Biology of Leukemias

Approximately 50% of de novo acute leukemias have distinctive molecular abnormalities, most frequently chromosomal translocations (1,2). These translocations typically involve genes that are involved in transcription and differentiation (3). As a result of the translocation, these genes are disrupted and the 5’-segment of one gene is joined to the 3’-end of a second gene to form a novel fusion gene, from which chimeric mRNA is transcribed and protein is translated. Inversions occur as well, which also create fusion genes from which novel proteins are generated (1,3). In contrast, many of the known translocations that occur in chronic leukemias and malignant lymphomas affect proto-oncogenes, which are involved in cell proliferation or survival, and an antigen-receptor gene. As a result of the translocation, the proto-oncogene is brought into proximity with the involved antigen receptor gene locus, typically without disrupting the coding region of the proto-oncogene. Under the influence of the antigen-receptor gene enhancers or promoters, the proto-oncogene is constitutively expressed, resulting in increased expression (overexpression) of the normal (nonmutated) protein (1,3). A common theme in such translocations are errors in the normal recombinational mechanisms involving the antigen-receptor genes.