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IgA nephropathy (IgAN) has been anecdotally reported in association with atypical hemolytic uremic syndrome (aHUS). The association likely portends poor renal outcome, and the possible relationship with complement overactivation has yet to be elucidated. We evaluated a series of IgAN patients with aHUS and reviewed the available literature. Adult patients who received a diagnosis of IgAN and developed aHUS between January 2009 and December 2019 were included in this retrospective review. We identified six IgAN-aHUS patients, all of whom developed end-stage kidney disease. At aHUS presentation all patients had decreased serum C3 levels. Predisposing pathogenetic variants and risk haplotypes for aHUS in CFH gene heterozygosity were documented in four out of six patients. Anti-CFH antibodies were found to be negative in the five tested patients. In the literature we identified 21 case reports involving aHUS-IgAN and six retrospective studies evaluating the presence of TMA at the time of renal biopsy. Hypertension, severe proteinuria, reduced sC3 and a worse renal prognosis were the common features of most cases. Our case series and literature review show that the onset of either aHUS or renal TMA in the course of IgAN are associated with very poor renal outcome. Activation of the alternative pathway revealed by consumption of serum C3 seems to play a major role. Our hypothesis is that the presence of a predisposing factor (e.g. dysregualtion of complement alternative pathway and/or other intrarenal precipitating factors) might be at the heart of aHUS-IgAN pathophysiology.

NO abstract available- Case report

Objective:To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC).Methods:We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry.Results:A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p < 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (>70%) ( p = 0.007) and PD-L1 expression >10% on TILs ( p = 0.024).Conclusions:mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro.Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy.Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs.Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.

Background and Aims IgG4 related disease (IgG4 RD) is a recently recognized systemic immune-mediated disorder. Pathophysiology of the disease is still unclear. It is characterized by fibro-inflammatory damage of the tissues, IgG-4 positive plasma-cells and often by elevated serum IgG4. This systemic disease can potentially affect every organ. Renal involvement can include tubulo-interstitial nephritis (TIN), membranous glomerulopathy (MGP) and retroperitoneal fibrosis. The epidemiology is still poorly described, but the disease seems more frequent in men over 50 years of age. Only few cases of IgG4 RD are reported in pediatric patients. Method We describe the first case of IgG4 related kidney disease (IgG4 RKD) in a child with concomitant bone marrow failure. Results M.C., a 2 year-old child, was diagnosed in 2017 with a trilinear bone marrow failure (HB 7.2 g/dL; PLT 6.000/mmc; PMC 923/mmc). Bone marrow biopsy showed poor and dyshomogeneous cellularity (20%) and lymphoplasmacytic infiltrate organized in two follicular structures. All investigations performed to rule out inherited bone marrow failure were negative (DEB test, telomere lenght measurement, c-Mpl mutation analysis, mithocondrial DNA analysis) IgG subclass analysis showed elevated serum levels of IgG4 subclass (353 mg/dL- normal level < 120 mg/dL). During the hospitalization, kidney failure with tubular acidosis was also found (creatinine 1.3 mg/dL, eGFR 28.5 mL/min/1.73 mq, bicarbonate 8.3 mEq/L). Urine analysis showed microematuria, proteinuria (1.07 g/L) and granular casts. Renal ultrasound did not demonstrate abnormal findings. A renal biopsy was performed and a kidney sample with up to 40 glomeruli was obtained. Light microscopy (H&E, JSM, PAS and Masson’s trichrome stains) showed tubule-interstitial inflammatory infiltrate (mainly composed of lymphoplasmacytic cells), irregular thickening of the glomerular basement membranes. IHC stains for C4D showed subepithelial deposits (++). IF was negative for IgA, IgM, C4 and C1q while showed subepithelial glomerular membrane IgG deposits (+++) with granular pattern and tubular wall deposits; glomerular deposits (+) and focal tubular deposits (+++) of C3. A diagnosis of MGP associated with TIN was made. IHC staining for IgG4 was also performed, which demonstrated plasmacells with overlapping positivity for IgG and IgG4. After the diagnosis of IgG4 RKD, an immune-suppressive therapy with steroids (1 mg/kg/die)– targeting both the haematological disorder and glomerulopathy - was started, without clinical response. Thereafter the patient underwent bone marrow transplant from HLA-identical family donor. Conclusion GMP indeed is a very uncommon disease in childhood. Moreover, the association of GMP with TIN is reported in few cases in the literature. Only in the last decade some case of TIN and GMP have been recognized as IgG4 RD and few cases have been reported in adults of IgG4 RKD with simultaneous TIN and GMP. To exclude primary GMP we will perform also the research of antiPLA2r1 antibodies in kidney biopsy. However, the specificity of antiPLA2r in children is lower than in adults and the association of primary GMP with IgG4 TIN is unlikely. IgG4 RD is an emerging systemic disease and it should be taken into account in differential diagnosis in systemic auto-immune diseases, also in the pediatric age. IgG4 RKD and bone marrow failure IgG4 RD are very rare in children but its real incidence among pediatric patients could be still underestimated.

Aim: The knowledge of the immune context of renal cell carcinoma (RCC) is useful to predict benefit from immunotherapy. We retrospectively characterized the immune context of RCC patients underwent primary nephrectomy and pulmonary metastasectomy. Materials & methods: Intratumoral infiltrating lymphocytes and peritumoral renal infiltrating lymphocytes, lymphocyte subpopulations (CD4+, CD8+), PD-1, PD-L1 were explored in paired samples of primary RCC (T) and respective pulmonary metastases (M). Results: The immune variables demonstrated intralesional and intratumoral heterogeneity. Intralesional lymphocyte heterogeneity reached 76% of cases in T, 28% in M. The heterogeneity rate for PD-L1 expression was from 44% (T) to 56% (M); it correlated with better survival. Conclusion: The immune context of RCC is highly variable both within a given tumor and among primary and metastases.

Background and objectives Complement alternative pathway (cAP) activation has recently been recognized as a key pathogenic event in ANCA-associated vasculitis (AAV). cAP dysregulation is also a major determinant of thrombotic microangiopathies (TMA), which can in turn complicate AAV. We explored the prognostic significance of cAP activation and of histologic evidence of TMA in a cohort of patients with renal AAV. Design, setting, participants, & measurements We studied 46 patients with AAV diagnosed between January 1990 and December 2011 at the Nephrology Unit of Parma University Hospital; 30 of them had undergone renal biopsy. We analyzed serum levels of C3 (sC3) and C4 (sC4) and, for 19 patients who had frozen plasma, plasma Bb and C5b-9 levels. We also reviewed all kidney biopsy specimens, specifically searching for histologic signs of TMA, and performed immunofluorescence or immunohistochemistry for C3d, C4d, Bb and C5b-9. Results sC3 was below the lower limit of normal in 35% of the patients, whereas C4 was low in only 2%. Patients with low sC3 tended to be older (P=0.04) and to have lower eGFR at diagnosis (P=0.06). The median follow-up was 78 months (interquartile range, 18–135 months); 18 patients reached ESRD (10 of 14 and 8 of 26 in the low and normal sC3 groups, respectively). Death-censored renal survival was lower in the low sC3 group than in the normal sC3 group (log-rank test, P=0.01). Eight of the 30 patients who had undergone biopsy (27%) had histologic signs of TMA; these signs were more frequent in patients with low sC3 (5 of 10 versus 3 of 20; P=0.04). Notably, patients with histologic signs of TMA had a dramatically worse death-censored renal survival than patients without TMA (log-rank test, P=0.01), with ESRD occurring in 8 of 8 patients with TMA versus 8 of 22 patients without TMA. Conclusions Low sC3 levels and histologic signs of TMA are associated with a poor renal prognosis in patients with AAV.

Background Primary or secondary glomerulonephritis has been anecdotally reported in association with atypical haemolytic uraemic syndrome (aHUS). We here report a series of six patients who developed aHUS and glomerulopathy, and review the literature on aHUS and glomerulonephritis. Methods Out of all patients diagnosed at our unit with biopsy-proven glomerular diseases between March 2007 and October 2011, selected cases developing aHUS during the follow-up are presented. The following tests were performed in all six patients: serum C3 and C4 levels, ADAMTS13 activity, CFH levels and anti-CFH autoantibodies and genetic screening for CFH, MCP, CFI, C3 and CFHR1-3 mutations and risk haplotypes associated with aHUS. Results Two hundred and forty-eight patients received a biopsy-proven diagnosis of glomerulopathy and were followed for a median of 31 months (range 2-58). Of these, six developed aHUS, within a median of 15 months (range 1-36) of their initial diagnosis of glomerulopathy. One of these patients had focal segmental glomerulosclerosis (FSGS), two membranoproliferative glomerulonephritis (MPGN) type I, one C3 glomerulonephritis and two systemic small vessel vasculitis [one granulomatosis with polyangiitis (Wegener's), one Henoch-Schoenlein purpura]. Five patients (one of them heterozygous for a CFH mutation) carried, in homo- or heterozygosity, the risk haplotype CFH-H3 (CFH tgtgt), previously described to be associated with aHUS, while another one patient was homozygous for the MCPggaac risk haplotype predisposing to aHUS when present on both alleles. Conclusions Different types of glomerulopathies can be complicated by aHUS. Several mechanisms can contribute to this association, such as nephrotic-range proteinuria, mutations or aHUS-risk haplotypes involving genes encoding alternative complement regulatory proteins in some patients and inflammatory triggers associated with systemic immune-mediated diseases.

We report the third case of bilateral metastatic renal meningeal hemangiopericytoma (HPC) 16 years after initial intracranial presentation. A 47-year-old male patient presented with abdominal mass drew our attention. Computed tomography (CT) demonstrated bilateral renal masses and another mass caudal to the lower pole of left kidney from which it was separated. He had a previous history of meningeal HPC. Since 1996, he underwent four neurosurgical operations and three CyberKnife radiosurgery. He underwent bilateral nephron sparing surgery. Histopathology study deposed for HPC. After 12 months, a CT scan revealed three hepatic lesions, which resulted comparable with HPC metastasis at a fine needle biopsy. An imaging-guided radiofrequency ablation was programmed. The patient is metastatic disease-free after 46 months. Previous history of meningeal HPC in patient with kidney masses should raise the suspicion of renal metastasis. The treatment of choice is surgery. In these cases, abdominal imaging should be included in the follow-up.

Complement protein factor H (CFH) is a regulatory protein of the alternative complement pathway (AP); CFH mutations lead to a spectrum of different phenotypical manifestations of renal disease.We report the case of a boy with a novel CFH gene mutation who presented with a membranoproliferative (MPGN) pattern of glomerular injury and developed 2 years later atypical hemolytic uremic syndrome (aHUS); this description shows that CFH alteration leads to two different renal diseases in the same patient.Our case suggests the possibility that complement dysregulation could determine different renal conditions, which may be part of the same disease spectrum. Early recognition of an evolution of glomerulopathies into aHUS may allow appropriate management and prevention of life-threatening consequences.

Renal bone metaplasia (RBM) is a uncommon condition and is often an incidental finding. The pathogenesis of this phenomenon is not clearly understood. The radiological signs described are not always present and the diagnosis is challenging. In the literature, there is no any conclusion about the optimal management of this condition due to the absence of some conclusions regarding its etiology. In our opinion, no treatment should be applied to prevent its possible evolution into urolithiasis. Surgical removal of the RBM is an overtreatment for a phenomenon not understood and potentially insignificant. We report our experience with a watchful waiting approach in a case of incidental diagnosis of RBM. After 3 years, the patient is asymptomatic, with no evidence of malignancies evolution, new renal stones or growth of the residual RBM.

This report analyses the clinicopathologic features of three metastatic extragenital neoplasms to the cervix. These examples of metastatic extragenital malignancies to the cervix are cutaneous malignant melanoma, colorectal carcinoma, and breast carcinoma. The diagnosis of these metastatic malignancies was suspected on a historical basis. The value of Pap smears is limited on the other hand, since for a correct diagnosis in all our cases, this examination required corroboration by histological and immunohistochemical analysis. In all these examples of extragenital metastatic neoplasms, as in other cases reported in literature, the patients had undergone cervical smear because of vaginal bleeding, even if Pap smear is considered a questionable maneuver in vaginal bleeding. Accordingly, our article reveals that a great deal of rigorous screening, precise morphological analysis, and plentiful clinical data are mandatory in approaching diagnoses of extracervical malignancies. However, this study did demonstrate that cytology does not alter patient management or outcome. In effect, in accordance with other studies, our cases of metastatic extragenital neoplasms to the uterus have poor prognosis.

Long-term toxicological experiments with inhibitors of acid secretion were found to induce hyperplasia and eventually carcinoid tumors of the enterochromaffin-like cells of the oxyntic mucosa. To evaluate the effects of 6 months' treatment with omeprazole in humans, the oxyntic endocrine cells were morphometrically investigated at the ultrastructural level in five patients with active duodenal ulcer. No omeprazole-induced changes were found in the volume density of the total endocrine cell population and specific cell types (including the enterochromaffin-like cell) as well as in the other cytological parameters investigated (number of cell profiles per unit area, mean cross-sectional area of cell profiles, nuclear-cytoplasmic ratio, and density of cytoplasmic secretory granules). Both pretreatment and post-treatment values in our patients with duodenal ulcer significantly differed from those of a previous investigation of healthy volunteers with regard to the volume density of enterochromaffin-like cells and non-granulated cells, which increased, and of D cells, which markedly decreased. The latter result may provide a cellular basis for impairment in the paracrine release of fundic somatostatin in peptic ulcer disease. Finally, morphometric data on endocrine cell volume density provided by electron microscopy were found to correlate with those obtained in the same patients using light microscopy techniques (Grimelius silver impregnation and chromogranin A immunostaining). It is concluded that 6 months' treatment with pharmacological doses of omeprazole is devoid of appreciable trophic effect on endocrine cells of human oxyntic mucosa.

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Ad una moderna classificazione istopatologica dei tumori vengono demandate molteplici qualita che comprendono una valenza di linguaggio universale ed un significato prognostico-terapeutico, associati ad una solida base istogenetica e contenuti, ove possibile, patogenetici. Appare chiaro come la “classificazione ideale” sia un obbiettivo difficile e talora impossibile da raggiungere.

Combined nonneuroendocrine–neuroendocrine lung tumors are relatively infrequent and little is known as for their genetic basis. Here, we report the case of a 69-year-old male with a solitary neoplasm in the upper lobe of the right lung. At histological examination, the tumor showed two components. The main part was an adenocarcinoma of the acinar type. The second part showed morphological and immunohistochemical phenotype of a neuroendocrine carcinoma composed of a small cell lung carcinoma and a large cell neuroendocrine carcinoma. The aim of our study was to investigate the genetic relationship between neuroendocrine and nonneuroendocrine tumor components. To this purpose, we performed a loss of heterozygosity (LOH) analysis with 40 chromosomal microsatellite markers. Microallelotyping revealed a common genetic profile in the different tumor areas. In 9 of 30 informative regions analyzed, LOH involved the same allele in all components, regardless of their histological type and grade. These findings support the true combined nature of this exocrine–neuroendocrine carcinoma of the lung and suggest a common monoclonal origin from a pluripotent epithelial (alveolar or bronchial) precursor cell for the two different tumor components.

We present a case of poorly differentiated endocrine carcinoma (PDEC) of the rectum identified immunohistochemically and characterized by a high degree of cellular pleomorphism, including bizarre giant cells. This case indicates that gastrointestinal PDECs are not restricted to small cell carcinomas. Among the multiple genes investigated, loss of heterozygosity (LOH) of the p53 locus without p53 immohistochemical accumulation, overexpression of c-kit and absent expression of p16 were seen.

Fine-needle aspiration (FNA) biopsy is increasingly used in the diagnosis and biological characterization of breast carcinomas in patients who receive preoperative chemotherapy. In this context, nuclear cytologic grade supplemented by DNA content could play an important role in the morphologic assessment of breast cancer. In this study, DNA ploidy pattern, analyzed by flow cytometry on FNAs from 92 primary breast carcinomas, was related to cytologic nuclear grade. Twenty-seven samples were cytologic grade 1, 33 were grade 2, and 32 were grade 3. Ploidy correlated with cytologic nuclear grade (P = 0.0001). Thirty percent of grade 1, 55% of grade 2, and 84% of grade 3 tumors were DNA aneuploid. For 30 of the 92 FNAs, it was possible to compare nuclear cytologic grade with the corresponding histologic grade using the Scarff, Bloom, and Richardson system. A high concordance (80%) between nuclear grade on FNAs and histologic grade was found. DNA flow cytometry in combination with nuclear cytologic grade might represent additional information for the characterization of breast cancer diagnosed by FNA.

SUMMARY Methods: The effects of three months of treatment with octreotide on gastric acid hypersecretion induced by hypergastrinaemia were investigated in patients with Zollinger-Ellison syndrome (n= 5) or antral G-cell hyperfunction (n= 4). Gastric acid secretion, fasting plasma gastrin concentrations and clinical findings were examined, and a morphometrical analysis of oxyntic endocrine cells was performed. Results: Administration of octreotide 100 meg b.d. subcutaneously significantly decreased the volume density of argyrophil cells (P < 0.05) as well as basal and pentagastrin-stimulated acid secretion (P < 0.05). Although partial or complete loss of inhibition was found in most patients after 3 months, gastrin levels were decreased during the first 2 months of treatment (P < 0.05). Fundic D-cells were not affected by treatment. Positive correlations were observed between volume density of argyrophil cells and basal acid output (r= 0.65); plasma gastrin and basal acid output (r= 0.74); plasma gastrin concentrations and volume density of argyrophil cells (r= 0.80). Conclusion: These results support the important role of the enterochromamn-like cell in maintaining acid secretion, and indicate a specific role for octreotide in the therapy of gastric acid hypersecretion associated with hypergastrinaemic diseases.

The aim of the study was to evaluate whether treatment with 200 micrograms/d of the somatostatin analogue octreotide (SMS 201-995) for three months can influence the trophic action exerted by hypergastrinemia on endocrine cells of the oxyntic mucosa, a condition potentially leading to hyperplasia and carcinoid tumors. Endocrine cells were morphometrically investigated in Grimelius silver stained sections of endoscopic biopsies of oxyntic mucosa collected from 13 hypergastrinemic patients with Zollinger-Ellison syndrome (ZES) (n = 5), antral G cell hyperfunction (AGCH) (n = 4) and atrophic gastritis type A (AG-A) (n = 4) before and after 3 months treatment and 3 months after drug discontinuance. The treatment induced a reduction of the volume density (P < 0.015), profile cross sectional area (P < 0.05) and number of cell profiles per unit area (P < 0.015) of argyrophil cells. A rebound of all these parameters was observed 3 months after drug withdrawal with values usually exceeding those at the entry, except in cases of AG-A. The patients' plasma gastrin concentrations presented similar variations showing a significant relation with all morphometric parameters of argyrophil cells. Also, the cell content in alpha subunit of human chorionic gonadotropin was related to the plasma gastrin levels, a finding confirming the close gastrin dependence of the expression of this protein by oxyntic endocrine cells. No significant changes were observed in mucosal somatostatin D cells. These results indicate that variations in circulating gastrin levels are the most likely factor responsible for the hypotrophic effect of octreotide on oxyntic argyrophil cells (mostly corresponding to the ECL cells) of hypergastrinemic patients.

Summary A solitary pedunculated polyp of the oxyntic mucosa removed from a 66-year-old patient with atrophic gastritis and achlorhydria exhibited distinctive histological features consisting of submucosal, mostly oxyntic-type glands with a smooth muscular framework. Histochemical and immunohistochemical studies demonstrated that the glands were composed of well differentiated chief, parietal, and endocrine cells. Moreover, less frequent glands of the antro-pyloric type were also seen. The lesion was regarded as a previously unrecognized variety of gastric hamartoma.

A case of multiple gastric carcinoids and nonantral atrophic gastritis in which the larger tumor was a composite carcinoid-adenocarcinoma is presented. The two components of the composite tumor immunohistochemically showed clear-cut diverging functional differentiations although the available evidence supported a common histogenesis from the metaplastic intestinal epithelium of the gastric mucosa. The carcinoid tissue of the composite tumor, which showed "atypical" features, also differed from the other, pure carcinoids, in which the histologic appearance was "typical." Total gastrectomy performed 1 month after the original gastric resection with antrectomy disclosed regressive changes in the endocrine cell proliferations of the gastric stump consistent with the withdrawal of a stimulating effect of the antral gastrin.

A comparative immunocytochemical investigation was performed on a series of 59 pancreatic endocrine tumours using a panel of seven markers for neuroendocrine neoplasms: neurone specific enolase (NSE), PGP 9.5, chromogranin A (CgA), PHE5, prealbumin (Pa), HISL-19, and alpha-subunit of human chorionic gonadotropin (alpha-HCG). Most markers can be separated into two groups characterized by an identical immunoreactive cellular compartment and substantial overlapping in the immunohistochemical results. The first group comprises soluble cytoplasmic proteins such as NSE and PGP 9.5 and is characterized by a diffuse, homogeneous staining of the cell cytoplasm that is not related to the type of hormone produced or the degree of cell differentiation. The second group includes antigens located in the cell secretory granules such as CgA, PHE5, Pa and HISL-19 and is characterized by a heterogenous, often polarized cell staining. The latter markers strongly react with benign glucagonomas and PP-omas and, in contrast with those of the former group, are strictly neuroendocrine-specific. However, they often are less effective in staining insulinomas and malignant tumours. An additional, distinctive and useful characteristic of the HISL-19 antibody was its ability to label the Golgi complex also in tumours with absent granular staining. Finally, alpha-HCG was found in 9 of 16 malignant tumours (mostly glucagonomas and insulinomas) and in 4 of 43 benign neoplasms (all insulinomas). The latter finding is not in accordance with the reputed specificity of the alpha-HCG expression by pancreatic endocrine tumours as a marker for tumour malignancy.

One hundred four endocrine tumors found in the body and tail of the pancreas of a patient with the Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia (MEN-I) were investigated by immunohistochemistry for insulin, glucagon, somatostatin, pancreatic polypeptide (PP), and gastrin. The results for each tumor were scored into six grades according to the frequency of immunoreactive cells. Pancreatic polypeptide, glucagon, insulin, and somatostatin were demonstrated in 96, 80, 62, and 42 tumors, respectively. When only the higher scores of cell frequency (3-5) were considered, PP and glucagon (accounting for 71 and 49 tumors, respectively) differed markedly from insulin (two tumors) and somatostatin (0). The frequency of PP-immunoreactive cells was higher in tumors of large size whereas that of glucagon cells was higher in the smaller neoplasms. No significant associations of the tumoral hormonal expressions were found with the type of histologic structure (trabecular versus gyriform), the occurrence of stromal fibrosis, and the intrapancreatic location of the neoplasms, except for a higher number of somatostatin cells in fibrotic tumors. Gastrin-immunoreactive cells never were found in the tumors in spite of the concomitant hypergastrinemia. In conclusion, the nonrandom expression of the hormonal phenotype by the neoplastic islet cells, as shown by the immunohistochemical, semiquantitative analysis of a large number of tumors, suggests that in our MEN-I patient the genetically determined neoplasms also are affected by other mechanisms, possibly nongenetic.

Previous studies have shown that hyperplastic endocrine cells of the oxyntic mucosa in patients with atrophic gastritis may express immunoreactivity for the alpha-subunit of human chorionic gonadotropin (alpha-HCG, common to all glycoprotein hormones). Since this endocrine proliferation is regarded as dependent on the trophic effect of the concomitant hypergastrinemia, the relation between immunohistochemical expression of alpha-HCG by oxyntic endocrine cells and serum levels of gastrin were investigated. The study was performed on endoscopic gastric biopsies of the oxyntic mucosa from 49 patients subdivided into the following groups: A) with histologically normal mucosa and normogastrinemia (22 cases), B) with atrophic gastritis and normogastrinemia (12 cases), C) with normal mucosa and hypergastrinemia (Zollinger-Ellison syndrome, retained antrum) (7 cases) and D) with atrophic gastritis and hypergastrinemia (with or without pernicious anemia) (8 cases). The alpha-HCG immunoreactive cells were found in all hypergastrinemic patients (groups C and D), regardless of the concomitant pathological condition of the mucosa. These cells accounted for 7.8% to 44.7% of the number of Grimelius argyrophil cells in consecutive serial sections. In contrast, alpha-HCG-containing cells were exceptional or absent in most normogastrinemic patients. Their number was sizable in only two cases of group A and three cases of group B, where it ranged from 2.5% to 14.8% of the number of argyrophil cells. It was concluded that expression of alpha-HCG is another feature of oxyntic endocrine cells associated with hypergastrinemia in addition to those previously recognized such as development of hyperplasia and/or carcinoid tumors.

Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D1 cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D1 cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D1 and P cells, if any, remains obscure.

The morphological and functional characteristics of the endocrine cells of the oxyntic (acid-secreting) mucosa of the human stomach, a target of the trophic effect of gastrin, are reviewed. In healthy subjects these cells account for 0.90 +/- 0.35% of the volume of the entire mucosa and for 1.21 +/- 0.44% of the volume of the epithelial mucosal component alone. The cells show no extension to the glandular lumen and show an intimate anatomic relationship with contiguous non-endocrine epithelial cells. This configuration indicates undefined local functions of the paracrine type not influenced by the gastric lumen content. Seven cell types were identified ultrastructurally, three of which (enterochromaffin-like (ECL), P and D) cumulatively account for more than 75% of the total endocrine cell mass. The secretory product(s) of the endocrine cells has not been demonstrated definitively with the exception of minor cell populations producing glucagon (only in the fetal life), somatostatin and 5-HT. Recently, production of histamine and glycoprotein hormone alpha-subunit by oxyntic endocrine cells of man have been reported. However, histamine seems to occur in these cells normally, whereas the production of glycoprotein hormone alpha-subunit appears to be virtually restricted to cells of patients with hypergastrinaemic conditions.

In 1969 Rubin1 described a proliferation of endocrine cells in the atrophic oxyntic (or fundic) mucosa of patients with pernicious anemia (PA). Shortly thereafter, Solcia et al.2 also noted hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG), even in the absence of PA, and, in addition, they reported a case of severe proliferation of the same cells in a patient with Zollinger—Ellison syndrome (ZES). These findings were confirmed in our laboratory,3,4 and we observed that hypergastrinemia is the common feature of the two otherwise opposite pathologic conditions of the oxyntic mucosa of the stomach. Considering the trophic effects of gastrin, therefore, we proposed that hypergastrinemia is responsible for the hyperplastic response of endocrine cells of the oxyntic mucosa in both CAG and ZES.4 The subsequent study of single cases of fundic carcinoid tumors extended this hypothesis by linking hypergastrinemia to the development of neoplasms from the same endocrine cell population.5,6

Two cases of multiple islet cell tumors mostly composed of glucagon-producing cells and associated with severe ulcer disease are presented. Multiple endocrine neoplasia type I (MEN-I) was present in both patients, although symptomatically latent in case 2. Immunohistochemistry showed that glucagon (A) cells were a major cell population (i.e., accounting for at least 30% of the tumor cell population) in 24 of 43 tumors (either macroadenomas or microadenomas) studied in case 1 and in 12 of 17 tumors studied in case 2. A major pancreatic polypeptide (PP) cell population was found in 12 and 7 tumors of case 1 and 2, respectively. In contrast, insulin (B) and somatostatin (D) cells were scarce in most adenomas. Gastrin-producing cells were not identified in any tumors, despite the use of different antigastrin antisera. Extrapancreatic or residual gastrinomas were not found at postmortem examination in case 1 or on appropriate surgical inspection done 24 years after the onset of the ulcer disease in patient 2. On the basis of these and of 17 additional cases collected in the literature, it is concluded that multiple A-cell tumors of the pancreas are an expression of the MEN-I and are mostly associated with ulcer disease and/or with hypergastrinemia of frequent uncertain origin. The mechanisms regulating the nonrandom phenotypic hormonal differentiation of these genetically determined tumors remain unknown.

An ultrastructural morphometric study of the endocrine cells of the oxyntic mucosa of the stomach in gastric biopsies collected from five male and five female healthy volunteers aged 19-31 was performed. No sex-related differences were disclosed. Endocrine cells accounted for 1.2 +/- 0.4% of the epithelial volume and 0.9 +/- 0.4% of the mucosal volume, i.e., including the lamina propria. After classification of the specific endocrine cell types according to the ultrastructural morphology of secretory granules, the volume densities of ECL, P and D cells (30 +/- 9%, 24 +/- 7%, and 22 +/- 4% of the entire endocrine cell mass, respectively) were higher than those of other endocrine cell types. In particular, EC cells contributed less than 10% and X cells represented a very low proportion of the total cells. Non-granulated profiles of cells which in all other respects appeared to be endocrine were also found with a volume density of 8 +/- 4%. D cells were distinguished by the high fraction of cytoplasm occupied by secretory granules (31 +/- 5%). Subdivision of the whole mucosa into four horizontal segments revealed the endocrine cells to be mostly distributed in the three lower, with virtually no endocrine cells in the superficial segment. The quantitative ultrastructural analysis of the endocrine cell population of the normal human oxyntic mucosa provided by this study may allow a better evaluation of physiological and pharmacological variations of the endocrine cell population.

Eighteen cases of severe hyperplasia of fundic argyrophil cells observed during routine histologic examination of endoscopic gastric biopsy specimens from unselected patients with upper gastro-intestinal symptomatology were investigated. All patients, except one, were female with a mean age of 57 years. Atrophic gastritis of fundic mucosa with severe hypo- or achlorhydria was present in all cases. Hypergastrinaemia (of antral origin) was found in 15 subjects in which circulating gastrin levels were determined. Pernicious anaemia was seen in 1 patient. At light microscopy, the hyperplastic fundic cells were stained by the Grimelius and the Sevier-Munger silver methods and, in approximately 30% of cases, by lead-haematoxylin. In addition, these cells reacted with anti chromogranin antibodies. In 8 of 9 patients studied by electron-microscopy, enterochromaffin-like (ECL) cells were found to be the more frequent cell type. D1 cells prevailed in 1 case and were rare in the others. The frequency of P cells was intermediate between that of ECL cells and that of D1 cells. In conclusion, our observations indicate that: argyrophil cell hyperplasia of atrophic fundic mucosa is prevalently found in women with hypergastrinaemia, and the hyperplastic process involves mostly the ECL type of gastric endocrine cells. It is noteworthy that similar associations have been shown to be present in patients affected by fundic carcinoid tumours and atrophic gastritis.