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Biomedical subjects

A B Gelb

Publications and source records attributed to A B Gelb.

At least 37 records · Page 2Linked to original sources
PubMed1994

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.

Adult↗
PubMed1994

Detection of immunophenotypic abnormalities in paraffin-embedded B-lineage non-Hodgkin's lymphomas.

The authors analyzed the frequency of immunophenotypic abnormalities in 1,474 cases of routinely fixed, paraffin-embedded B-lineage non-Hodgkin's lymphomas. B-lineage was determined by immunoreactivity for CD20 (L26, 92%); CD45RA (4KB5, an additional 3%) or immunoglobulin (Ig) light chain restriction (remaining 5%). CD45RA was found to be especially helpful on Bouin's-fixed or decalcified tissue and Ig staining was most helpful in plasmacytoid lesions. Coexpression of the T-cell marker CD43 (Leu-22) was the most common immunophenotypic abnormality, seen in 60% of mantle cell lymphomas (MCL), 39% of CLL/small lymphocytic lymphomas, 16% of diffuse large cell lymphomas (DLCL), but only 5% of follicular lymphomas (FL). Antibodies to CD45RO (A6 and UCHL1) and CD3 (polyclonal) were useful in distinguishing infiltrating T cells from B cells coexpressing CD43. Ig light chain restriction was the next commonest immunophenotypic abnormality, which was identified in 67% of plasmacytoid diffuse small cell lymphomas, 43% of MCLs, 35% of monocytoid B-cell lymphomas and 28% of FLs. Overexpression of bcl-2 oncogenic protein was observed in 71% of FLs (n = 96), but not in a control group of reactive follicular hyperplasias (n = 34). Combining two criteria increased the sensitivity of immunodiagnosis in certain circumstances.

Antigens, CD↗
PubMed1993

Adenine phosphoribosyltransferase deficiency with renal deposition of 2,8-dihydroxyadenine leading to nephrolithiasis and chronic renal failure.

Homozygous adenine phosphoribosyltransferase deficiency is a genetic defect that is associated with 2,8-dihydroxyadenine urolithiasis. Since the prevalence of the heterozygous state is found in 0.4% to 1.2% of the population, it is surprising that more cases of 2,8-dihydroxyadenine urolithiasis have not been reported. Herein we describe a patient with complete adenine phosphoribosyltransferase deficiency with 2,8-dihydroxyadenine urolithiasis leading to chronic renal failure. Gene sequencing revealed that the patient is a compound heterozygote. One of the mutations (a T insertion between bases 346 and 347) has been encountered before, but the second (a G-to-A substitution at base 1356) has not been previously reported. Possible explanations for the unexpected rarity of 2,8-dihydroxyadenine urolithiasis are discussed.

Adenine↗
PubMed1993

Infantile histiocytoid cardiomyopathy--myocardial or conduction system hamartoma: what is the cell type involved?

Primary myocardial diseases in the pediatric age group encompass a variety of metabolic, infectious, congenital, and acquired disorders, one of which is "histiocytoid cardiomyopathy." We describe clinical and pathologic features in two infants. Autopsy findings in the first case were consistent with sudden cardiac death. The second infant has survived for 2 years on antiarrhythmic therapy with amiodarone. Microscopically, cells with vacuolated to granular cytoplasm were grouped in fascicles, imparting a pseudonodular appearance, but following a distribution reminiscent of conduction fibers. Ultrastructurally, the cells lack a T-tubule system, possess scattered lipid droplets and desmosomes rather than side-to-side junctions, and contain leptomeric fibrils that predominantly marginate to the cell periphery without sarcomeres. Immunostaining of paraffin-embedded tissue reveals perimembranous immunoreactivity for muscle-specific actin, but not for the histiocytic markers CD68 (KP1) and lysozyme. Immunohistochemistry may be a practical alternative when tissue is not saved for electron microscopy. The clinical and pathologic features of this disorder in light of the current literature suggest that it may be hamartoma, possibly of conduction system origin.

Actins↗
PubMed1993

Stage I renal cell carcinoma. A clinicopathologic study of 82 cases.

Stage has been established as the most important predictor of prognosis in renal cell carcinoma. The predictive value of other morphologic features is less well established. Therefore, in this study we assessed morphologic parameters in 82 Robson stage I renal cell carcinomas. Insufficient numbers of T1 lesions were present in this series to permit a confident comparison of Robson staging with the Union Internationale Contre le Cancer-American Joint Committee on Cancer TNM (tumor, node, metastasis) staging. Morphologic parameters--including size, character of cytoplasm, nuclear grade, and pelvic invasion--were studied. Both univariate survival analysis and multivariate or tree-structured survival analysis (TSSA) were employed, with disease-free survival and actuarial survival as end points. Nuclear grade was the most important predictor of prognosis in stage I neoplasms by TSSA. Nuclear grade greater than 2 correlated with significantly shorter survival (p = 0.018). Stage I tumors measuring less than 5.0 cm by survival analysis (or 6.0 cm by TSSA) were associated with improved disease-free survival (p = 0.040), although TSSA indicated that the effect was pronounced only in low-grade neoplasms. The character of cell cytoplasm was not independent of nuclear grade (Kruskal-Wallis test, p = 0.028). The contingency table indicated disproportionate numbers of grade 4 mixed cell tumors, grade 3 granular cell tumors, and low-grade clear cell tumors. By TSSA, younger patients with low-grade but larger tumors had a poor clinical outcome. Elderly patients with high-grade tumors had the worst overall survival. None of the other clinical parameters or architectural pattern correlated with survival or disease-free survival. When nuclear grade was combined with tumor size and age at diagnosis in a decision tree, patients with stage I neoplasms were separated into favorable, intermediate, and poor prognosis groups.

Adult↗
PubMed1993

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

Recent literature suggests that usual Hodgkin's disease (nodular sclerosing and mixed cellularity types or UHD) and nodular lymphocyte predominance Hodgkin's 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 mixed-cellularity Hodgkin's disease (MCHD), two with nodular sclerosis Hodgkin's 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.

Adult↗
PubMed1993

Leu 7 (CD57) reactivity distinguishes nodular lymphocyte predominance Hodgkin's disease from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma and follicular lymphoma.

Several recent reports have suggested that nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct from other forms of Hodgkin's disease and may be more closely related to B-cell non-Hodgkin's lymphoma. This is primarily based on immunophenotypic studies that have shown that the L & H cells in NLPHD demonstrate a B-cell phenotype. In 1989, Poppema reported that the T cells in NLPHD differ from T cells in other forms of Hodgkin's disease in that they demonstrate reactivity for Leu 7 (CD57). In this study we tested the hypothesis that Leu 7 (CD57) reactivity of small lymphocytes in NLPHD is an immunophenotypic feature that distinguishes NLPHD from nodular sclerosing Hodgkin's disease and from certain B-cell lymphomas that may histologically simulate NLPHD, namely T-cell-rich B-cell lymphoma and follicular lymphoma. Using an image analysis method, we found Leu 7 (CD57) reactivity in an average of 18.9% of the small lymphocytes in the nodules of NLPHD compared with 3.9% in nodular sclerosing Hodgkin's disease, 4.3% in T-cell-rich B-cell lymphoma, and 2.1% in follicular lymphoma. Moreover, Leu 7 (CD57)-reactive small lymphocytes often showed a distinctive pattern in NLPHD, forming a ring of cells around the large L & H cells. While scattered Leu 7 (CD57)-reactive lymphocytes were found in the other disorders, the percentage of reactive cells and the pattern of reactivity were significantly different in NLPHD. These results suggest that Leu 7 (CD57) reactivity may be used as an additional immunophenotypic criterion in distinguishing NLPHD from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma, and follicular lymphoma. The clinical and biological significance of Leu 7 (CD57) reactivity of small lymphocytes in NLPHD merits further investigation.

Antigens, Differentiation↗
PubMed1993

Lymphocytes infiltrating primary cutaneous neoplasms selectively express the cutaneous lymphocyte-associated antigen (CLA).

The cutaneous lymphocyte-associated antigen (CLA) is the T-cell ligand for E-selectin and is involved in tissue selective migration of memory/effector T cells to chronic inflammatory sites in skin. Here, we examine the hypothesis that CLA is also involved in the local host immune response to cutaneous neoplasms. Eleven primary cutaneous melanomas, nine primary cutaneous squamous cell carcinomas, and 11 assorted neoplasms metastatic to cutaneous and noncutaneous sites were immunostained with anti-CLA (HECA-452), as well as antibodies directed against B cells (CD20), T/NK cells (CD43), and memory/effector T cells (CD45RO). Essentially all of the lymphocytes surrounding and infiltrating both the cutaneous and noncutaneous tumors were CD43+/CD20-, and most expressed the memory/effector marker CD45RO. CLA was expressed on 10 to 80% (mean: 50%) of T cells associated with primary cutaneous neoplasms (including both melanomas and squamous cell carcinomas) but was essentially absent from noncutaneous primaries (including those metastatic to dermis) and from cutaneous primaries metastatic to dermis or other sites. Overall, the results suggest that CLA+memory T cells are a major component of the local host immune response to cutaneous neoplasms and are likely recruited to the skin by site-specific rather than tumor-specific mechanisms. The lack of a CLA+T-cell response to dermal metastases suggests that epidermal involvement may be required to attract this subset.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1993

Major histocompatibility complex class I and class II antigen expression in diffuse large cell and large cell immunoblastic lymphomas. Absence of a correlation between antigen expression and clinical outcome.

The major histocompatibility complex (MHC) class I (HLA-A, B, C) and class II (HLA-DR) antigens are involved in cell-to-cell recognition and in regulating the immune response. Others have shown previously that MHC class I and class II antigens may be absent in a subset of malignant lymphomas, prompting the hypothesis that the absence of MHC antigen expression may be one of the mechanisms involved in the growth and dissemination of malignant lymphomas (by allowing a neoplasm to escape immune surveillance). To address this hypothesis, we analyzed MHC class I and class II (HLA-DR) antigen expression by diffuse large cell and large cell immunoblastic lymphomas in 88 and 117 patients, respectively, using frozen sections and the monoclonal antibodies W6/32 (HLA-A, B, C), anti-beta 2-microglobulin, and L203 (HLA-DR). Although there were no statistically significant clinical differences by MHC class II antigen expression, a small group of patients with MHC class I antigen-negative lymphomas were significantly younger (P = 0.03), less often had small neoplasms (P = 0.03), and were treated with doxorubicin-based chemotherapy more frequently (P = 0.04) than those with antigen-positive lymphomas. However, neither MHC class I nor class II antigen expression by the lymphomas consistently correlated with patient survival or freedom from relapse. This lack of correlation was true for all patients assessed, as well as for the subsets of patients with B-cell lymphomas, T-cell neoplasms, or those treated with doxorubicin-based chemotherapy. In accordance with previously published studies, stage, presence of B symptoms, and treatment with doxorubicin-based chemotherapy were of prognostic importance in univariate or multivariate analyses for survival or freedom from relapse. The findings may be considered evidence against the hypothesis that the absence of MHC class I or II antigen expression by malignant lymphomas plays a role in their tumorigenicity. However, we cannot completely exclude the possibility that the therapies used for this group of patients may have obscured any effect that MHC antigen expression exerts on prognosis.

Adolescent↗
PubMed1992

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.

Adenine↗
PubMed1992

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.

Adult↗
PubMed1992

Estimation of tumor growth fractions in archival formalin-fixed, paraffin-embedded tissues using two anti-PCNA/Cyclin monoclonal antibodies. Factors affecting reactivity.

Immunohistochemical detection of cell cycle-related markers for estimation of tumor growth fractions using paraffin-embedded tissue sections would have applications in experimental and clinical pathology as an in situ histologic alternative to flow cytometry. The monoclonal antibodies 19A2 and PC10 detect the proliferating cell nuclear antigen (PCNA/Cyclin), an auxiliary protein to DNA polymerase-delta. In a prospective group of uniformly handled, formalin-fixed malignant lymphomas we previously demonstrated 19A2 to be a reliable marker of proliferative activity similar to Ki-67 in frozen tissue. The present study examines the applicability of this technique in archival formalin-fixed material. Studies on tonsilar tissue revealed that formalin fixation beyond 30 hours adversely affected reactivity of 19A2, possibly explaining the variable results in nonuniformly fixed archival material. We found that only 27 (56%) of 48 archival cases of infiltrating ductal carcinoma showed sufficient reactivity with 19A2 to permit reliable quantification of the tumor growth fraction. Acid pretreatment with 2N HCl had no apparent effect on 19A2 reactivity. Using both antibodies on a group of 32 archival lymphomas, carcinomas, and sarcomas, significantly more biopsies stained reliably for PC10 (84%) than for 19A2 (72%; P < 0.036). Further, none of the cases that did not react with PC10 reacted with 19A2. PC10 may recognize a different epitope of PCNA/Cyclin which may be more resistant to alterations by fixation. In the 23 cases that reliably stained for both markers, largely carcinomas, there was excellent correlation between estimated growth fractions (r = 0.96). Although immunostaining provides a useful way to estimate tumor growth fractions in paraffin-embedded tissues, modifications of technique and cautious interpretation of results are advisable when using archival material.

Antibodies, Monoclonal↗
PubMed1991

27-year mortality in the Western Collaborative Group Study: construction of risk groups by recursive partitioning.

The relationship of selected biological and behavioral characteristics measured at baseline examination to 27-year mortality due to coronary heart disease (CHD), cancers of all sites, and total mortality in the 3154 men that form the Western Collaborative Group Study was investigated using tree-structured survival analysis or recursive partitioning (RP). Intake (1960-61) characteristics included in the present analyses were age, serum cholesterol, systolic blood pressure (SBP), cigarette smoking, body mass index (BMI), Type A/B behavior, and behavioral hostility. Tree-structured survival analysis for CHD mortality partitioned the cohort into six groups and identified five groups with distinct survival experience. Exceptionally high CHD mortality rates (17.3 and 14.6 per thousand) were experienced by 89 older men with elevated hostility ratings and SBP less than or equal to 150, and 238 men whose initial SBP was greater than 150 mmHg. Younger men (age less than or equal to 48) with SBP less than or equal to 150 and with serum cholesterol levels greater than 227 had a death rate of 4.8 per thousand, compared with a rate of 1.7 in similar men with lower cholesterol levels. Applied to 27-year cancer mortality, the RP algorithm partitioned the cohort into four distinct survival groups. Younger (age less than 45) Type B men had superior survival compared with Type A men of similar ages, and the proportion of ever cigarette smokers in these two groups was not statistically different. The results obtained by tree-structured survival analyses were compared with results obtained by Cox regression survival analyses.

Adult↗
PubMed1990

Cellular DNA profiles of benign and malignant adrenocortical tumors.

We evaluated the DNA content of 43 adrenocortical neoplasms by flow cytometry and related it to histopathologic criteria of malignancy and survival. Tumor tissue was selected from paraffin blocks and processed by a modification of the Hedley technique. The tumors were classified as adenomas and carcinomas by the criteria of Weiss. Aneuploid stem-lines were identified in nine of 13 (69%) of the carcinomas and in six of 30 (20%) of the adenomas. Five of the six patients with aneuploid adenomas are alive and well (mean follow-up, 59 months); the sixth was lost to follow-up. Although there was a significant correlation between ploidy and histologic diagnosis (p = 0.041), the sensitivity and specificity of aneuploidy for predicting clinical outcome were only 56% and 65%, respectively. In addition, there was no significant difference in survival between patients with diploid versus aneuploid tumors, despite a highly statistically significant difference in survival between patients with a histologic diagnosis of adenoma versus carcinoma (p = 0.00080). We found correlations between ploidy and tumor size, mitotic rate, and nuclear grade (p = 0.0033, p = 0.0017, and p = 0.018, respectively). There was also a significant correlation between the proliferation fraction of a tumor and its nuclear grade (p = .0093), but not its mitotic count or clinical outcome. Because both adrenal adenomas and carcinomas may contain abnormal DNA stem-lines, ploidy alone is not a reliable discriminator in individual cases.

Adenoma↗
PubMed1989

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.

Adult↗
PubMed1988

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.

Adenoma↗
PubMed1987

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.

Actuarial Analysis↗