Association of Clear Cell Likelihood Score on MRI and Growth Kinetics of Small Solid Renal Masses on Active Surveillance.

BACKGROUND. The lack of validated imaging markers to characterize biologic aggressiveness of small renal masses (SRMs)-defined as those categorized as cT1a and 4 cm and smaller-hinders medical decision-making among available initial management strategies. OBJECTIVE. The purpose of this article was to explore the association of the clear cell likelihood score (ccLS) on MRI with growth rates and progression of SRMs. METHODS. This retrospective study included consecutive SRMs assigned a ccLS on clinical MRI examinations performed between June 2016 and November 2019 at an academic tertiary-care medical center or its affiliated safety net hospital system. The ccLS reports the likelihood that the SRM represents clear cell renal cell carcinoma (ccRCC) from 1 (very unlikely) to 5 (very likely). The ccLS was extracted from clinical reports. Tumor size measurements were extracted from available prior and follow-up cross-sectional imaging examinations, through June 2020. Serial tumor size measurements were fit to linear and exponential growth curves. Estimated growth rates were grouped by the assigned ccLS. Tumor progression was defined by development of large size (> 4 cm in at least two consecutive measurements) and/or rapid growth (doubling of volume within 1 year). Differences among ccLS groups were evaluated using Kruskal-Wallis tests. Correlations between ccLS and growth rate were evaluated by Spearman correlation (ρ). RESULTS. Growth rates of 386 SRMs (100 ccLS 1-2, 75 ccLS 3, and 211 ccLS 4-5) from 339 patients (median age, 65 years; 198 men, 141 women) were analyzed. Median follow-up was 1.2 years. The ccLS was correlated with growth rates by size (ρ = 0.19; p < .001; ccLS 4-5, 9%/year; ccLS 1-2, 5%/year; p < .001) and by volume (ρ = 0.14; p = .006; ccLS 4-5, 29%/year; ccLS 1-2, 16%/year; p < .001). Disease progression (observed in 49 SRMs) was not significantly associated with ccLS group (p = .61). Two patients (0.6%) developed metastases during active surveillance: one ccLS 1 was a type 2 papillary renal cell carcinoma and one ccLS 4 was ccRCC. CONCLUSION. Growth is associated with ccLS in SRMs, with higher ccLS correlating with faster growth. CLINICAL IMPACT. SRMs with lower ccLS may be considered for active surveillance, whereas SRMs with higher ccLS may warrant earlier intervention. The noninvasive ccLS derived from MRI correlates with growth rate of SRMs and may help guide personalized management.

Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation.

The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.

Subsets of transgenic T cells that recognize CD1 induce or prevent murine lupus: role of cytokines.

T cells with T cell receptor (TCR) transgenes that recognized CD1 on syngeneic B cells stimulated B cells to secrete immunoglobulins in vitro. The CD4+, CD8+, or CD4-CD8- T cells from the spleen of the TCR transgenic BALB/c donors induced lupus with anti-double stranded DNA antibodies, proteinuria, and immune complex glomerulonephritis in irradiated BALB/c nude mice reconstituted with nude bone marrow. Injection of purified CD4-CD8- T cells from the marrow of transgenic donors prevented the induction of lupus by the transgenic T cells. Transgenic T cells that induced lupus secreted large amounts of interferon (IFN)-gamma and little interleukin (IL)-4, and those that prevented lupus secreted large amounts of IL-4 and little IFN-gamma or IL-10.

Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease.

Sorted CD4(+) and CD8(+) T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2(b)) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell-depleted donor marrow cells, into lethally irradiated BALB/c (H-2(d)) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1(+) T cells represented <1% of all T cells in the blood and approximately 30% of T cells in the marrow, the capacity of sorted marrow NK1.1(-) CD4(+) and CD8(+) T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1(+) T cells suppressed GVHD. The marrow NK1.1(+) T cells secreted high levels of both interferon gamma (IFN-gamma) and interleukin 4 (IL-4), and the NK1.1(-) T cells secreted high levels of IFN-gamma with little IL-4. Marrow NK1.1(+) T cells obtained from IL-4(-/-) rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1(-) and NK1.1(+) T cell subsets via their differential production of cytokines.

Monocyte haptotaxis induced by the RANTES chemokine.

BACKGROUND: Soluble mediators and inducible cell-surface molecules coordinate the ordered cascade of events giving rise to inflammation. The specific mechanisms underlying the attraction of antigen-specific cells into a site of inflammation remain sketchy, however. In particular, it is unclear how chemoattractants cause rapidly moving immune cells to adhere to the blood vessel wall and to enter inflamed tissues. RESULTS: Here we show that RANTES, a potent chemo-attractant for monocytes and T lymphocytes, is inducibly expressed within an inflamed organ, binds to endothelial cells, and promotes haptotaxis, the migration of cells induced by surface-bound gradients. CONCLUSION: These findings lead us to propose a model for the role of RANTES in the migration of antigen-specific immune cells into an inflammatory site.

Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft.

Postischemic filtration failure in experimental animals results primarily from depression of the transcapillary hydraulic pressure difference (delta P), a quantity that cannot be determined in humans. To circumvent this limitation we determined the GFR and each of its remaining determinants in transplanted kidneys. Findings in 12 allografts that exhibited subsequent normofiltration (group 1) were compared with those in 11 allografts that exhibited persistent hypofiltration (group 2). Determinations were made intraoperatively in the exposed graft after 1-3 h of reperfusion. GFR (6 +/- 2 vs 29 +/- 5 ml/min) and renal plasma flow by Doppler flow meter (140 +/- 30 vs 315 +/- 49 ml/min) were significantly lower in group 2 than group 1. Morphometric analysis of glomeruli obtained by biopsy and a structural hydrodynamic model of viscous flow revealed the glomerular ultrafiltration coefficient to be similar, averaging 3.5 +/- 0.6 and 3.1 +/- 0.2 ml/(min.mmHg) in group 2 vs 1, respectively. Corresponding values for plasma oncotic pressure were also similar, averaging 19 +/- 1 vs 21 +/- 1 mmHg. We next used a mathematical model of glomerular ultrafiltration and a sensitivity analysis to calculate the prevailing range for delta P from the foregoing measured quantities. This revealed delta P to vary from only 20-21 mmHg in group 2 vs 34-45 mmHg in group 1 (P < 0.001). Further morphometric analysis revealed the diameters of Bowman's space and tubular lumens, as well as the percentage of tubular cells that were necrotic or devoid of brush border, to be similar in the two groups. We thus conclude (a) that delta P depression is the predominant cause of hypofiltration in this form of postischemic injury; and (b) that afferent vasoconstriction rather than tubular obstruction is the proximate cause of the delta P depression.

Outcome of the acute glomerular injury in proliferative lupus nephritis.

Treatment with total lymphoid irradiation (TLI) and corticosteroids markedly reduced activity of systemic lupus erythematosis in 10 patients with diffuse proliferative lupus nephritis (DPLN) complicated by a nephrotic syndrome. Physiologic and morphometric techniques were used serially before, and 12 and 36 mo post-TLI to characterize the course of glomerular injury. Judged by a progressive reduction in the density of glomerular cells and immune deposits, glomerular inflammation subsided. A sustained reduction in the fractional clearance of albumin, IgG and uncharged dextrans of radius greater than 50 A, pointed to a parallel improvement in glomerular barrier size-selectivity. Corresponding changes in GFR were modest, however. A trend towards higher GFR at 12 mo was associated with a marked increase in the fraction of glomerular tuft area occupied by patent capillary loops as inflammatory changes receded. A late trend toward declining GFR beyond 12 mo was associated with progressive glomerulosclerosis, which affected 57% of all glomeruli globally by 36 mo post-TLI. Judged by a parallel increase in volume by 59%, remaining, patent glomeruli had undergone a process of adaptive enlargement. We propose that an increasing fraction of glomeruli continues to undergo progressive sclerosis after DPLN has become quiescent, and that the prevailing GFR depends on the extent to which hypertrophied remnant glomeruli can compensate for the ensuing loss of filtration surface area.

Backleak, tight junctions, and cell- cell adhesion in postischemic injury to the renal allograft.

Postischemic injury in recipients of 3-7-d-old renal allografts was classified into sustained (n = 19) or recovering (n = 20) acute renal failure (ARF) according to the prevailing inulin clearance. Recipients of optimally functioning, long-standing allografts and living donors undergoing nephrectomy served as functional (n = 14) and structural controls (n = 10), respectively. Marked elevation above control of fractional clearance of dextrans of graded size was consistent with transtubular backleak of 57% of filtrate (inulin) in sustained ARF. No backleak was detected in recovering ARF. To explore a structural basis for backleak, allograft biopsies were taken intraoperatively, 1 h after reperfusion in all recipients, and again on day 7 after transplant in a subset (n = 10). Electron microscopy revealed disruption of both apical and basolateral membranes of proximal tubule cells in both sustained and recovering ARF, but cell exfoliation and tubule basement membrane denudation were negligible. Histochemical analysis of membrane-associated adhesion complexes confirmed an abnormality of proximal but not distal tubule cells, marked in sustained ARF but not in recovering ARF. Staining for the zonula occludens complex (ZO-1) and adherens complex (alpha, beta, and gamma catenins) revealed diminished intensity and redistribution of each cytoskeletal protein from the apico-lateral membrane boundary. We conclude that impaired integrity of tight junctions and cell-cell adhesion in the proximal tubule provides a paracellular pathway through which filtrate leaks back in sustained allograft ARF.

Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas.

Gastric cancer can be divided into two histologic types: intestinal and diffuse. To determine whether Helicobacter pylori, a bacterium linked with gastritis, was associated with either cancer type, we reviewed histologic sections from stomachs of patients who had undergone gastrectomy for gastric cancer. Of 37 of the sections with evidence of intestinal-type cancer, 33 (89.2%) contained H pylori in noncancerous tissue compared with 7 (31.8%) of 22 of the sections with evidence of diffuse-type cancer (odds ratio = 17.7; P less than .001). This association remained strong when controlled for age, sex, site, and number of sections reviewed. The prevalence of H pylori in intestinal-type gastric cancer far exceeded the prevalence of H pylori in diffuse disease and that described in the normal US population. This finding suggests that H pylori may be a cofactor in development of intestinal-type gastric cancer.

Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients.

The lymphoproliferative processes that developed in five renal transplant recipients were studied in an attempt to characterize and classify them morphologically. Nine surgical specimens, hematological material on all patients, and autopsy specimens from three patients were available. Studies performed included: conventional histopathology; evaluation of cell markers (immunoglobulins and sheep erythrocyte, complement, and Fc receptors) and cytoplasmic immunoglobulins (peroxidase-antiperoxidase technique); ultrastructural examination; and karyotype analysis. The lymphoid lesions in our patients shared marked cytological polymorphism (small and large cells, of both follicular center and "medullary" type) and polyclonal B-cell features, which indicated a common reactive nonneoplastic origin. However, other features, such as morphological atypia of the immunoblasts, extensive necrosis, chromosomal aberrations, and an incipient monoclonal component suggested the development of lymphoma in some of these lesions. In contradistinction, the abundance of typical immunoblasts was a feature that seemed to correlate with the clinical activity of the disease rather than with the biological malignancy. The multiplicity of B-cell types and the presence of a follicular center cell component with diffuse distribution, as well as the extensive necrosis in the malignant forms, seem to differentiate morphologically the lymphoproliferative processes arising in transplant recipients from both the hyperplasias and the lymphomas developing in immunologically normal hosts. For the former, we propose the terms of "polymorphic diffuse B-cell hyperplasias" and "polymorphic B-cell lymphomas."

Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia.

A comparison of the late effects on intellectual and neuropsychologic function of three different CNS "prophylaxis" regimens was conducted in 104 patients treated for childhood acute lymphocytic leukemia. Of the children studied, 33 were randomized to treatment with intrathecal (IT) methotrexate alone, 36 to IT methotrexate plus 2,400 rad cranial irradiation, and 35 to IT methotrexate plus intravenous intermediate dose methotrexate. All patients were in their first (complete) continuous remission, were a minimum of one year post-CNS prophylaxis and had no evidence of CNS disease at the time of evaluation. In contrast to the other two treatment groups, children whose CNS prophylaxis included cranial irradiation attained significantly lower mean Full Scale IQs (P less than .001), performed more poorly on the Wide Range Achievement Test, a measure of school abilities, and exhibited a greater number of difficulties on a variety of other neuropsychologic measures. The poorer performance of the irradiated group was independent of sex of the patient, time since treatment and age at diagnosis. These data suggest that the addition of 2,400 rad cranial irradiation to CNS prophylaxis in ALL puts these children at greater risk for mild global loss in intellectual and neuropsychologic ability.

Recurrence of disease in pancreas transplants.

In a series of 200 pancreas transplants with 6 mo to less than 9 yr of follow-up, recurrence of disease was identified as the cause of graft failure in 8 cases, all in non- or minimally immunosuppressed recipients of transplants from identical twin (n = 3) or HLA-identical sibling (n = 5) donors. Recurrence of disease was defined as selective loss of beta-cells; other endocrine cell types persisted and appeared normal within the islets of the graft. Isletitis was present in islets with residual beta-cells during the evolution of the process in all nonimmunosuppressed and in some immunosuppressed recipients, but isletitis resolved in all cases in which beta-cell destruction was complete and also resolved in some cases in which residual beta-cells were retained after the introduction of or an increase in immunosuppression. Recurrence of disease can be prevented by immunosuppression, and 2 recipients of identical twin grafts and 12 recipients of grafts from HLA-identical siblings had functioning grafts as of March 1988, the longest greater than 7 yr. The process has not been observed in patients in whom full-dose immunosuppression has been used, including HLA-identical siblings, and this may be the reason no cases of recurrence of disease have been identified in recipients of cadaveric grafts. Alternatively, the observations are consistent with, but not proof of, the hypothesis that recurrence of disease (autoimmune isletitis leading to diabetes) is a major histocompatibility complex-restricted phenomenon.

Reduction of aortic wall motion inhibits hypertension-mediated experimental atherosclerosis.

Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.

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.

Immunotactoid glomerulopathy.

We present 11 patients with immunotactoid glomerulopathy, a new syndrome characterized clinically by proteinuria (11/11), microscopic hematuria (9/11) and hypertension (9/11). The patients consisted of six females and five males, aged 25 to 59 years (mean, 44.6). Proteinuria was the presenting feature and the reason for renal biopsy in all patients. The diagnosis of immunotactoid glomerulopathy was established at renal biopsy by the presence of glomerular extracellular microtubules composed of immune reactants. All the biopsies studied by immunofluorescence (10 cases) had glomerular deposits of IgG and C3. In three biopsies studied with IgG subclass specific antisera, only one patient had monoclonal immunoglobulin deposits (IgG3 kappa). In six cases the glomerular deposits were analyzed for light chains. In three the deposits contained kappa only, and three consisted of both kappa and lambda. In two cases the immune aggregates were confined to the mesangium, and in the remaining eight cases, the deposits were present in the mesangium and the glomerular basement membranes. Electron-dense deposits composed of microtubules were present in the same distribution within the glomerulus as the immune reactants. The microtubules had a uniform diameter in each biopsy, but they varied in size from case to case. They were approximately the same size in eight cases (mean, 22.3 +/- 3 [SD] nm). Three cases had much larger microtubules: 34.2 nm, 35.4 nm, and 48.9 nm in diameter. Although the 22.3-nm microtubules resembled amyloid in their appearance, glomerular distribution and random orientation in the tissue, they were more than twice the diameter of amyloid (8.9 nm), and Congo red and thioflavin T stains for amyloid were negative. Similar microtubular structures have been described in patients with cryoglobulinemia, SLE and paraproteinemia, but these diseases were excluded in our patients on clinical, serologic and in some cases histologic grounds. More important, none of our patients had clinical or histochemical evidence of amyloidosis, an entity which may be confused with immunotactoid glomerulopathy on a morphologic basis. Follow-up, from 22 to 94 months (mean, 52.6) was obtained in all 11 patients, and 2 clinical courses were noted. Six patients had progressive deterioration of renal function, with five requiring dialysis. This group had severe hypertension (4/6) and nephrotic-range proteinuria (5/6) at some point in their course. The remaining five patients with stable renal function had proteinuria of less than 2.0 g/24 hr in most cases (4/5), and none had severe hypertension. This dichotomy correlated with the distribution of immunotactoids.(ABSTRACT TRUNCATED AT 400 WORDS)

Renal vascular lesions after chemotherapy with vinblastine, bleomycin, and cisplatin.

A 30 year old man with metastatic embryonal carcinoma became hypertensive during vinblastine, bleomycin, and cisplatin therapy. Three months after completion of therapy, accelerated hypertension occurred (blood pressure 210/140 mm Hg). Nitroprusside failed to control the hypertension, but captopril resulted in a prompt and sustained normalization of the blood pressure. The plasma renin activity was markedly elevated before therapy. Renal biopsy disclosed "onionskin" narrowing of the interlobular arteries and fibrin thrombosis of a majority of the afferent arterioles. A form of drug-induced renovascular hypertension is suggested.

Diffuse intrapulmonary hemorrhage and glomerulonephritis unrelated to anti-glomerular basement membrane antibody.

Nine patients with diffuse intrapulmonary hemorrhage and glomerulonephritis not due to anti-glomerular basement membrane (anti-GBM) antibody are described and similar previously reported cases are reviewed. Eight patients were seen during a four-year interval and represented 47 percent of the cases of pulmonary hemorrhage and glomerulonephritis seen during this period. Diagnoses included systemic vasculitis of unspecified type in two patients with seropositive rhematoid arthritis, idiopathic crescentic glomerulonephritis with negative immunofluorescence in two, Wegener's granulomatosis in two, and polyarteritis nodosa, Henoch-Schönlein purpura, and mixed connective tissue disease in one each. Differentiation from anti-GBM antibody-mediated pulmonary hemorrhage and glomerulonephritis by clinical evaluation alone was frequently difficult, emphasizing the importance of both immunopathologic studies and evaluation of serum for anti-GBM antibody in all patients with pulmonary hemorrhage and glomerulonephritis. In eight of nine patients, significant episodes of pulmonary hemorrhage improved markedly within 24 to 72 hours following initiation of high-dose corticosteroid therapy. In contrast, renal function did not improve in the majority of patients.

Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 cases.

Twenty-one examples of neuroendocrine carcinoma of the skin were examined by the unlabeled antibody enzyme method for several neural hormones and peptides, carcinoembryonic antigen, S-100 protein, neuron-specific enolase, and three intermediate filaments: neurofilament, glial fibrillary acidic protein, and cytokeratin. Vasoactive intestinal polypeptide from two sources reacted with the neoplastic cells of four (18%) and seven (32%) of the cases, and pancreatic polypeptide reacted with scattered cells of one case. Neuron-specific enolase reactivity occurred in 50% of the cases. Neurofilament (70, 150, 200 kilodaltons) was strongly positive in 40% of the tumors whereas neurofilament (200 kilodaltons) was negative. Two monoclonal anticytokeratin antibodies of 54 kilodaltons and 44-54 kilodaltons reacted in 77% and 64% of the cases, respectively, in a distribution similar to the neurofilament. Sections reacted with antisera against cytokeratins of higher molecular weight were negative. The demonstration of vasoactive intestinal polypeptide, pancreatic polypeptide, neurofilament, and neuron-specific enolase is evidence of the neuroendocrine nature of this neoplasm.

Duodenal gangliocytic paraganglioma. An immunohistochemical and ultrastructural study and a hypothesis concerning its origin.

We report the immunohistochemical and ultrastructural features of three duodenal gangliocytic paragangliomas and compare them with duodenal carcinoid, extra-adrenal paraganglioma, pheochromocytoma, and ganglioneuroma. The gangliocytic paraganglioma is characterized by polygonal or columnar epithelial cells, ganglion cells, and spindle cells. The epithelial cells stained for neurofilament, neuron-specific enolase, pancreatic polypeptide, and somatostatin in three cases; leu-enkephalin, molluskan cardioexcitatory peptide, and vasoactive intestinal peptide in two; and glucagon and insulin in one case each. The ganglion cells were positive for leu-enkephalin, neurofilament, neuron-specific enolase, pancreatic polypeptide, and somatostatin in three cases, and glucagon in one. The spindle cells stained for neurofilament, neuron-specific enolase, and S-100 protein. Although there was some overlap in immunoreactivity between the gangliocytic paraganglioma and the other tumors examined, our data indicate that the gangliocytic paraganglioma is a distinctive lesion. We propose that it is a hyperplastic or neoplastic proliferation of 1) endodermally derived epithelial cells originating from the ventral primordium of the pancreas, 2) neuroectodermal ganglion cells, and 3) neuroectodermal spindle cells (Schwann cells).

Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrastructural study of 43 cases.

The clinical and pathologic features of 43 cases of primary neuroendocrine carcinoma of the skin are reported. These tumors arise in the dermis and subcutaneous tissues of elderly individuals. The head and neck are the most common primary sites followed by the lower and upper extremities and trunk. Characteristic histologic features include round cells with scanty amphophilic cytoplasm and vesicular nuclei with multiple small nucleoli. The cells are arranged in sheets, solid nests, or anastomosing trabeculae. Collections of perinuclear intermediate filaments, cytoplasmic dense-core membrane-bound secretory granules, complex intercellular junctions, and cytoplasmic spinous processes are the principal fine structural features. These ultrastructural findings are similar to those of the normal cutaneous Merkel cell. The natural history of this neoplasm is characterized by local recurrence in 30% of cases, regional lymph node metastases in 65% of cases, and distant metastases in 40%. One-third of the patients were dead because of their tumors. Treatment of extensive local or distant metastatic disease with chemotherapy or radiotherapy resulted in only short-term palliative response.