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Among clinicians, the users of medical calculators have expanded in recent years to an unprecedented number. The usefulness of some of these calculators is sometimes debatable, and experienced professionals may at times be right in avoiding their use; however, many may simply be unaware of the very existence of medical calculators applicable to their field of interest. The authors felt that this latter scenario might possibly apply to hepatocellular carcinoma (HCC). Hence, the authors concisely reviewed 10 free online medical calculators proposed in the last 8 years, categorizing them on the basis of the purpose for which they were developed (risk of harboring or developing HCC, N=4; prognostication in established HCC, N=6). In addition, the authors tried to establish the success each calculator has had so far in the medical community, by 2 criteria: having been included in the more popular app of medical calculators and being highly cited in the scientific literature.

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Background Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. Methods Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer–specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. Results Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1–2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. Conclusion ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.

Background The risk of life-threatening complications, such as visceral disseminated varicella zoster virus (VZV) infection, is greater in immunosuppressed individuals, such as systemic lupus erythematosus (SLE) patients. Case presentation Here, a case is reported of a Caucasian woman diagnosed with lupus nephritis and anti-phospholipid syndrome, who was subjected to mycophenolate mofetil and high-dose steroid remission-induction therapy. Two months later she developed abdominal pain followed by a fatal rapid multi-organ failure. As no typical skin rashes were evident, death was initially attributed to catastrophic anti-phospholipid syndrome. However, autopsy and virological examinations on archival material revealed a disseminated VZV infection. Conclusions Overall, this case highlights the importance of having a high clinical suspicion of fatal VZV infections in heavily immunosuppressed SLE patients even when typical signs and symptoms are lacking.

Angioleiomyoma is a benign smooth muscle and vessel tumor; laryngeal localization is extremely rare with only 24 cases described in the literature; moreover, it should be considered in the differential diagnosis of laryngeal mass. Endoscopic complete surgical excision with dissection along capsule is now considered the gold-standard treatment for small and well-circumscribed laryngeal angioleiomyoma. We present a case of laryngeal angioleiomyoma successfully treated with carbon dioxide laser technology which resulted in a bleeding reduction and adequate hemostasis with less tissue damage and good functional outcome.

Serous effusions complicating the course of lymphomas occur commonly in the pleural space but seldom in the peritoneum, where they most often present as chylous ascites with diagnostic cytology. Almost invariably, in these rare cases, the serum to ascites albumin gradient is low. We describe a 28-year-old woman with anasarca, ascites and a serum to ascites albumin gradient of 1.1 g/dl, consistent with portal hypertension. No tumour cells were detected in the ascitic fluid. However, a CT scan of the chest and abdomen disclosed liver and spleen enlargement and multiple enlarged retroperitoneal lymph nodes, suspicious for a lymphoproliferative disorder. Bone marrow aspiration and biopsy were not diagnostic, so a decision was made to proceed with a splenectomy despite the onset of low-grade disseminated intravascular coagulation. Surgery was uneventful. Diffuse large B cell lymphoma was diagnosed. A liver biopsy taken at the time of surgery demonstrated that the liver parenchyma was massively infiltrated by reactive T lymphocytes surrounding rare large CD20+ tumour cells. This infiltrate had likely led to increased portal pressure attended by ascites formation, which resolved completely after chemotherapy. The case emphasizes the rewards of pursuing a diagnosis supported by a high prior probability even in the presence of apparently discordant laboratory findings, as well as the importance of performing a diagnostic splenectomy in case of splenomegaly with unexplained focal lesions. LEARNING POINTS Lymphomas may present with serous effusion, which is usually chylous and with positive cytology when represented by ascites accumulation; non-chylous effusions can be due to altered lymphatic drainage, extrinsic compression of the portal vein by enlarged lymph nodes as well as massive infiltration of the liver by lymphoma. If the cause of splenomegaly is unclear, diagnostic splenectomy remains a viable option. The diagnosis of lymphoma should always be pursued, even if it requires apparently unwise surgery, since this type of cancer can be treated effectively only if thoroughly characterized pathologically and molecularly. Keywords: Ascites, splenomegaly, lymphoma, disseminated intravascular coagulation, diagnostic splenectomy HOSPITAL GRAND ROUNDS Public University Hospital Maggiore della Carita, Novara, Italy by Editorial Board Member, Prof. Ettore Bartoli The Public University Hospital “Maggiore della Carita”, Novara, Italy, is a 700-bed teaching hospital, with 2700 employees. Approximately 500 of these are medical doctors. It is the home Institution for the Medical School of the “Universita del Piemonte Orientale”. In its early days it was a branch of the University of Turin and it became autonomous in 1998. Today, it admits 150 medical students and 80 interns a year and is strongly committed to pursuing excellence in education and research. In fact, according to the most recent CENSIS survey, it ranks 6th out of the 37 state universities nationwide. Despite its recent history as a university hospital, the roots of the “Maggiore” date back to the Middle Ages. Originally it was a charity institute dedicated to the Archangel Michael - hence the name “Casa di San Michele della Carita”. It was founded in the XI century with the aim of helping the poor, the elderly and the pilgrims. The care activity was addressed to aiding the sick only later, starting from the end of the thirteenth century. In 1482, a Bull of Pope Sixtus IV imposed the union between the Hospital of “S. Michele” with the other seven hospitals in Novara, confirming the importance assumed by this institution in its urban context. Open in a separate window CASE DESCRIPTION A 28-year-old woman was admitted to the internal medicine division of an academic hospital in northern Italy with complaints of progressive abdominal distention and fatigue. She also described substantial weight gain and anorexia over the previous 6 months. At physical examination, the patient appeared chronically ill. She was afebrile and all other vital parameters were normal, but there was anasarca, with marked swelling and erythema of the lower legs. There were no enlarged or palpable lymph nodes, but a protuberant abdomen, with central tympany and flank dullness at percussion, was noted. The remainder of the examination was normal. A full blood count revealed white blood cells (WBC) 7.69 ×109/l (81% neutrophils, 9% lymphocytes), red blood cells (RBC) 3.96×1012/l, haemoglobin 11.2 g/l, and platelets (PLTs) 143×109/l. Examination of a peripheral blood smear did not add significant information. Prothrombin time was 14.4 sec. Serological studies for human immunodeficiency virus, hepatitis B virus and hepatitis C virus were negative. Other laboratory results included lactate dehydrogenase (LDH) 688 IU/l (normal limits, 208–450 IU/l), total serum proteins 3.8 g/dl (6.4–8.3 g/dl), albumin 2.2 g/dl (3.5–5.5 g/dl) and total bilirubin 1.5 mg/dl (0.3–1.2 mg/dl). Renal function tests and electrolyte levels were normal. A paracentesis was performed with aspiration of a yellow-coloured, slightly turbid fluid whose analysis gave the following results: albumin 1.1 g/dl (serum to ascites albumin gradient of 1.1 g/dl), WBC 0.29×109/l, of which 31% were neutrophils and 69% lymphocytes, RBC 1000/μl, LDH 312 U/l (normal 105–245 U/l) and rare epithelial cells. Culture of the ascitic fluid and real time-polymerase chain reaction amplification for Mycobacterium tuberculosis were negative. A computed tomography (CT) scan of the abdomen and chest confirmed massive ascites, liver enlargement without focal lesions, thinning of the inferior vena cava and hepatic veins, enlargement of the spleen (longitudinal diameter, 15 cm) whose parenchymal architecture was distorted by several lesions (the largest being 5.38 cm in diameter), multiple enlarged retroperitoneal lymph nodes above the psoas muscle, small bilateral pleural effusions, and diffuse imbibition of the adipose tissue (Figs. 1 and ​and22). Open in a separate window Figure 1 Coronal view of a contrast-enhanced CT scan of the abdomen and chest, showing a distorted and enlarged spleen and a diffusely enlarged liver with no focal lesions

Basal cell carcinoma (BCC) is a common skin cancer worldwide. However, BCC of the nipple and areola complex is rare. Men are more affected than women. Most of the cases were treated with simple excision. We report a case of BCC of the right nipple-areola complex in a 75-year-old man, treated with Mohs surgery and simple mastectomy.

A 65-year-old man with chronic hepatitis C and no history of alcohol abuse was admitted to our liver unit for the recent development of massive ascites and presumed hepatorenal syndrome. In the preceding two weeks, he had received medical treatment for acute pancreatitis and cholecystitis. Abdominal paracentesis demonstrated a cloudy, orange peritoneal fluid, with total protein concentration 3.6 g/dl, serum-ascites albumin gradient 1.0 g/dl, and ratios of ascites-serum bilirubin and amylase approximately 8:1. Diagnostic imaging demonstrated no pancreatic pseudocysts. Ten days later, at laparotomy, acalculous perforation of the gallbladder was identified. After cholecystectomy, amylase concentration in the ascitic fluid dropped within a few days to 40% of serum values; ascites disappeared within a few weeks. We conclude that in the presence of a perforated gallbladder, pancreatobiliary reflux was responsible for this unusual combination of choleperitoneum and pancreatic ascites, which we propose to call pancreatobiliary ascites.

e14614 Background: Anti-PD-1/PD-L1 checkpoint inhibitors have shown preliminary evidence of activity in HCC. PD-L1 status is a putative predictor of response, however PD ligands expression can be heterogeneous across sampled sites, with implications in the development of immunotherapy. Methods: We constructed a tissue microarray from 77 patients: 56 with surgically resected and 21 with intermediate/advanced HCC in whom 20 matching metastases were also available. Tumour and surrounding cirrhosis were analysed for PD-L1 and PD-L2 expression by immunohistochemistry. FFPE-extracted RNA was analyzed on the NanoString nCounter system using 12 paired primary/metastatic HCC cores from 6 patients, with validation in a subset of further 24 specimens. Results: Surgically resected cases were Child A (51/56, 91%), BCLC A (45/56, 80%). In resected tumour cores 11/56 (20%) were PD-L1 and 18/56 (32%) were PD-L2 positive. Surrounding cirrhotic liver revealed PD-L1 in the lymphocytic infiltrate in 8/56 samples (14%), whilst PD-L2 expression was found in the cirrhotic background in 29/56 cases (52%). PD-L2 expression in cirrhotic (p = 0.03) but not in tumour cores (p = 0.13) correlated with more advanced BCLC stage. In patients with intermediate-advanced HCC (n = 21), the prevalence of tumour PD-Ls expression was 40% (8/21) for both markers. Concordance between PD-L1 positive primary and metastases was 33% and 85% in PD-L1 negative tumours. In contrast, there was universal concordance between in PD-L2 expression between primary and metastatic HCC (p < 0.001). Targeted transcriptomic profiling revealed a subset of 40 genes involved in innate and adaptive immunity to be differentially regulated across primary and metastatic disease. Conclusions: Intra-tumour heterogeneity in the expression of PD-L1 is common in HCC, whilst PD-L2 is homogeneously distributed in primary and metastatic deposits. Unsupervised transcriptomic profiling confirms differential activation of innate and adaptive immune-related pathways in the metastatic dissemination of liver cancer. This has profound implications in the clinical development of immune response biomarkers in HCC.

Neurofibromatosis type 1 could be associated with multiple gastrointestinal stromal tumours, although their presence is not considered among the major diagnostic criteria. We present here a case of a 50-year-old female complaining of abdominal pain, with about 100 small intestinal stromal tumours. This finding prompted us to suspect a neurofibromatosis which was clinically confirmed afterwards. Light microscopy examination revealed a low-grade stromal tumour with skeinoid fibres. Mixed neural-interstitial cells of Cajal origin or, alternatively, neural differentiation of interstitial cells of Cajal are discussed on the basis of immunophenotype (CD117+, CD34+) and ultrastructure. A 2-year follow-up did not indicate an aggressive course in the case of this neoplasm.

The bcl-2 proto-oncogene functions as a cell death suppressor, and its expression prolongs cell survival by blocking apoptosis. Data available on the clinical relevance of bcl-2 protein expression in patients with non-small-cell lung cancer (NSCLC) are controversial. We analysed the role of bcl-2 protein expression on 6-year relapse-free survival in 229 patients with stage I-IIIa NSCLC (101 squamous cell carcinomas and 128 adenocarcinomas) subjected to surgery, with curative intent. Immunohistochemical analysis was performed on archival material by using a monoclonal antibody anti-bcl-2 (clone 124). Bcl-2 protein expression, which was detected in 22% of the cases, was significantly related to stage, histology and grading, and was an indicator of clinical outcome. The probability of relapse-free survival at 6 years was longer for patients with bcl-2-positive tumours (74%) than for those with bcl-2-negative tumours (57%) (P=0.02). This finding was mainly evident for the subgroups of patients with stage IIIa tumours (P=0.05), squamous cell carcinoma (P=0.03) or moderately/poorly differentiated tumours (P=0.02). However, multivariate analysis by Weibull's regression model indicated that bcl-2 protein expression was not an independent prognostic risk factor in patients with curable NSCLC when the information provided by stage was available.

BACKGROUND In clinical breast cancer research, the utility of certain biomarkers as predictors of response to surgery, chemotherapy, or hormonal therapy has been studied intensively. Much less research has been done on the relevance of biologic predictors of response to radiotherapy, which represents an effective local-regional treatment for breast cancer. PURPOSE The utility of biomarkers involved in DNA damage repair (p53 protein), control of programmed cell death (p53 and Bcl-2 proteins), and cellular detoxification (glutathione S-transferase-pi [GST-pi] enzyme) in predicting local breast cancer recurrence was analyzed retrospectively in two cohorts of breast cancer patients. These patients had had no detectable metastases in the axillary lymph nodes (i.e., node-negative) or in distant sites and had had similar distributions of clinicopathologic and biologic prognostic features. They had been treated by conservative surgery alone (139 case patients) or by conservative surgery followed by adjuvant radiotherapy (496 case patients) during the period from 1984 through 1990. METHODS The expression of the p53, GST-pi, and Bcl-2 proteins in the specimens of primary breast tumor obtained from these patients was determined by use of immunohistochemistry; cell proliferation activity and levels of steroid receptors were determined by use of a [3H]thymidine-labeling index assay and the dextran-coated charcoal technique, respectively. The median time of follow-up of patients was 6 years. In the analyses of patient outcomes, only local failures that presented as first events were considered. RESULTS After surgery alone, the risk of local recurrence at 6 years was higher for patients with tumors exhibiting elevated levels of p53 and GST-pi protein expression than for patients with low levels (hazard ratio [HR] = 3.1, 95% confidence interval [CI] = 1.3-7.7, two-sided P = .012; HR = 2.7, 95% CI = 1.1-6.4, two-sided P = .026, respectively). Weak or no observable expression of Bcl-2 protein was only suggestive of a higher frequency of local failures. Adjustment for patient age, tumor size, cell proliferation, and estrogen receptor status did not change these findings. Conversely, in the series of patients given conservative surgery followed by radiotherapy, there was no difference in local tumor recurrence between patients with tumors expressing or not expressing each of the three markers. CONCLUSIONS Our study provides indirect evidence of a benefit from radiation therapy in preventing local breast cancer relapse, particularly among node-negative patients with tumors that express elevated levels of the p53 or GST-pi proteins or that express little or no Bcl-2 protein.

Pulmonary dirofilariasis is a rare entity caused by Dirofilaria, a dog worm that is transmitted to humans by mosquitoes. The filarial nematode enters the subcutaneous tissue, travels to the right ventricle, dies and then embolizes the pulmonary vessels causing a small pulmonary infarction, which subsequently appears as a solitary nodule. Although these nodules are usually identified incidentally by chest radiography in asymptomatic patients, the lesion is generally presumed to be neoplastic. Diagnosis is made by surgical excision. Awareness of this benign entity is important in the differential diagnosis of pulmonary coin-lesions.

Background: The aim of the study was to perform a comprehensive diagnostic evaluation of six popular, non-proprietary, indirect markers of liver fibrosis in a cohort of patients with chronic hepatitis C representing the full spectrum of disease severity. Methods: A total of 167 consecutive, hepatitis C virus RNA positive, untreated patients with chronic hepatitis C were studied. Liver biopsy with histological evaluation and age/platelet index, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, Bonacini's discriminant score, Forn's fibrosis index and Fibrolndex were assessed in all patients. Results: The area under the receiver operating characteristic curves of the six tests was always greater when performed to discriminate patients with METAVIR score F4 than when assessed to discriminate patients with METAVIR score >F2. At step-wise discriminant analysis the only indirect marker of fibrosis entered was Fibrolndex, with the following correct classification of the patients: total =52.1, patients with scores F0-F1 =62.2, patients with scores F2-F3=26.0 and patients with score F4=68.4. Conclusions: The ability to correctly classify patients using a panel of non-proprietary indirect markers of liver fibrosis is far from being ideal. Among them, Fibrolndex appears to possess the best discriminating capacity. The simultaneous use of several indirect markers of liver fibrosis does not improve their diagnostic accuracy.

We here report two new cases of human pulmonary dirofilariasis in men aged 62 and 64 from Northern and Central Italy, respectively. Both were asymptomatic and the infections were discovered incidentally when chest radiographs taken for another reason revealed the presence of a coin lesion. The initial clinical diagnosis was oriented towards a lung tumour, and an excisional lung biopsy after thoracotomy was necessary for the final diagnosis. Pathologically, the lesion consisted of a roundish subpleural infarct with a central thrombotic artery containing sections of an immature nematode: Dirofilaria repens was diagnosed histologically in one case, the necrotic condition of the worm allowing only genus identification, Dirofilaria, in the other case. In both samples, PCR analysis amplified a 246 bp product, specific for the IpS insert 11 of D. repens. The authors stress the role of PCR in the diagnosis of this parasite from paraffin samples, also in cases in which identification of the species was not possible by conventional morphology due to poor conservation of the worm. These cases represent the first PCR-based diagnosis of D. repens in a human pulmonary dirofilariasis on samples embedded in paraffin.

The frequency of various types of renal changes in patients with type 2 diabetes is not clearly defined in the literature. Reported discrepancies likely are caused by ethnic and geographic factors. However, policies used in nephrological centers for the selection of patients to undergo renal biopsy also may have an influence. The present study reports 393 renal biopsies in patients with type 2 diabetes performed in a group of centers in northwestern Italy using different (restricted [CRPs] or unrestricted [CUP]) biopsy policies. On the basis of light microscopic, immunofluorescence, and ultrastructural findings, cases were subdivided into three classes characterized by the presence of diabetic glomerulosclerosis (class 1), prevailing vascular (arterioarteriolosclerotic) and ischemic glomerular changes (class 2), other glomerulonephritides superimposed on diabetic glomerulosclerosis (class 3a), or glomerulonephritides without the presence of diabetic glomerulosclerosis (class 3b). Although no significant differences were found for class 2 (detected in 15% and 16% of patients from CRPs and the CUP, respectively), the frequency of the other two classes was strongly biased by the biopsy policy. Class 1 was found in 29% and 51% of cases, and class 3 in 57% and 33% of cases from CRPs and the CUP, respectively. Moreover, class 3a was more common (67%) in the CUP, and class 3b (78%) in CRPs. Our findings may explain conflicting data from the literature and the influence that type of adopted biopsy policy may have on an epidemiological evaluation. This study helps clarify the frequency of renal changes in patients with type 2 diabetes and suggests more extensive use of renal biopsy to obtain reliable prognostic indications and plan a rational therapeutic approach.

For breast cancer, many prognostic markers that initially appeared promising have failed to maintain their clinical predictive value. Few reports have analyzed the consistency over time of biological and clinical information provided by biomarkers. Tumour cell proliferation has acquired relevance as an indicator of prognosis and of response to treatment. Since its clinical role has been investigated for some decades, cell proliferation represents an ideal marker for an over-time validation. In 3,800 node-negative breast cancers recruited between 1972 and 1991, the consistency of information provided by the 3H-thymidine labelling index (TLI), in terms of basic relations with other clinico-pathological and biological variables and clinical predictivity, was evaluated using a combined analysis of results previously published by our group for distinct series of patients. Clinical predictivity was analyzed on a subset of 2,067 patients given local-regional therapy until relapse and followed for a median time from 6 to 10 years. Over the entire period TLI maintained a weak direct relation with tumour size and an inverse strong relation with steroid receptors. An increase in TLI was observed for tumours in post-menopausal patients up to the mid 1980s. During 3 different accrual periods (1972-1983; 1984-1987; 1988-1991), TLI was a consistent and independent predictor of relapse-free time, distant metastasis and overall survival, regardless of its consideration as a continuous variable or with a cutoff value of 3%. The reproducibility of our results over time provides support to the consistency of the methodology used and of the biological and clinical information obtained when using TLI as an indicator of breast cancer cell proliferation.

Two hundred and nineteen (33 GH, 21 GH-PRL, 38 PRL, 16 ACTH, 1 TSH cell functioning and 38 FSH-LH, 17 alpha-chain, 8 mixed, 27 minimal glycoprotein--MIN-GLYC--, 11 small argyrophil granule--SAG--, 4 silent TSH-sTSH--and 5 silent ACTH-sACTH--cell nonfunctioning) adenomas were investigated immunohistochemically with antibodies against ACTH, GH, PRL, TSH, FSH, LH alpha-hCG, chromogranin A (CgA) and chromogranin B (CgB). For immunostaining of CgB a novel monoclonal (B 11) antibody was employed. All types of adenomas were positive for CgB. CgA was widely expressed in nonfunctioning FSH-LH, MIN-GLYC, SAG, MIXED, alpha-chain adenomas and in the single TSH cell functioning adenoma. CgA was lacking both in PRL and ACTH functioning adenomas and was poorly expressed in GH and GH-PRL functioning adenomas. The distribution of Grimelius' silver paralleled that of CgA-IR, but not that of CgB-IR. We conclude that: 1) CgB may be considered as an universal granular marker for pituitary adenomas, 2) CgA is an important marker for nonfunctioning adenomas, 3) the pattern of distribution of CgA and CgB for most nonfunctioning ("null cell" according to Kovacs et al.) adenomas favors their origin from glycoprotein producing (FSH/LH, TSH) cells.

A previously well 60-year-old woman presented to hospital with a 3-week history of fatigue, anorexia, abdominal pain, nausea and vomiting, and a 4-kg weight loss. She had previously consulted her general practitioner about an episode of diarrhea and dark stools and was found at that time to have