A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Characteristics of 252 patients with bronchopulmonary neuroendocrine tumours treated at the Copenhagen NET Centre of Excellence.

BACKGROUND: Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). AIM: To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded). MATERIAL AND METHODS: Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS. RESULTS: 162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19-89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p < 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p < 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p < 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC. CONCLUSION: In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor.

Glassy cell carcinoma of the colon with human chorionic gonadotropin-production. A case report with immunohistochemical and ultrastructural analysis.

An unusual tumor in the descending colon with human chorionic gonadotropin-beta (HCG-beta) production and histological features of a "glassy cell" carcinoma is presented. Glassy cell carcinoma has been described in the uterus and fallopian tubes as well as the cervix, but in these locations the tumor is not HCG-beta producing. Glassy cell carcinomas have been described in some cases as having glandular and squamous differentiation as well as marked cellular pleomorphism. The tumors are generally associated with a poor prognosis.

Predicting prognosis of gastrointestinal smooth muscle tumors. Role of clinical and histologic evaluation, flow cytometry, and image cytometry.

Both flow cytometry (FCM) and morphometry have been proposed as techniques for predicting the prognosis of gastrointestinal (GI) smooth muscle tumors (SMTs). In particular, DNA aneuploidy by FCM has been associated with high histologic grade and shortened survival, whereas the DNA index determined by image cytometry has been proposed as a criterion for the diagnosis of malignancy. To further define the potential roles of these two techniques, we performed a variety of morphometric and FCM measurements on paraffin blocks from 122 patients with GI SMTs, with a median follow-up period of 6 years, together with assessments of tumor size and mitotic activity. None of the morphometric measurements (nuclear perimeter, area, form factor, longest diameter, average ferret diameter, equivalent diameter, and DNA index) was a significant prognostic factor when analyzed using a univariate Cox model. In contrast, the flow cytometric mean channel number, the fraction of cells in G2M, aneuploidy of the G0/G1 peak, aneuploidy of the G2M peak, tumor size, and mitotic activity index were statistically significant in univariate models, together with the patient age and sex, and whether or not the patient presented with metastases. In a multivariate model, > 10 mitotic figures per 50 high-power fields and metastases indicated a poor prognosis. If metastasis was not allowed to enter the model, the mitotic index and aneuploidy of the G2M peak portended a poor prognosis.

Intra-abdominal fibromatosis. A pathologic analysis of 130 tumors with comparison of clinical subgroups.

We studied the clinical, gross, and histologic findings of 130 fibromatoses of the mesentery and other peritoneal sites. Seventeen patients had Gardner syndrome, 12 had prior abdominal surgery, and six had apparent estrogen elevation, including five pregnant or postpartum women and an alcoholic male with gynecomastia. The tumors were usually large and grossly circumscribed. Most often, they were located in the mesentery of the small bowel. They were multiple in 18 cases. Typical histologic features included a dense, collagenous stroma; prominent, dilated, thin-walled vessels; muscular hyperplasia of small arteries; keloidal change; myxoid change; and fibrous tissue insinuation into the muscularis propria of the bowel. Although mitoses were noted in many tumors, they were usually few in number. The gross and histologic features were similar in the clinical subgroups; however, keloidal change was seen less often in female patients. Less than half of the cases were initially correctly diagnosed. Most patients without Gardner syndrome were without recurrence at follow-up, even when the lesions had been incompletely excised.

Carcinoids of the duodenum. A histologic and immunohistochemical study of 65 tumors.

The light-microscopic and immunohistochemical characteristics of 65 duodenal carcinoids are presented. Most tumors showed a mixture of cribriform, insular, glandular, solid, and trabecular growth patterns. Eighty-five percent of the tumors were argyrophil and 15% argentaffin. The nonspecific neuroendocrine markers chromogranin, Leu-7, and neuron-specific enolase were positive in 97, 91, and 83% of tumors, respectively. Immunoreactivity for specific hormones/amines were as follows (percent positive tumors): somatostatin, 47%; N-gastrin, 56%; serotonin, 39%; calcitonin, 19%; insulin, 5%; pancreatic polypeptide, 3%; adrenal corticotropic hormone, 0%; glucagon, 0%. Sixty-eight percent had gastrin/cholecystokinin-like reactivity. Ten psammomatous tumors were located near the ampulla; eight were somatostatin positive, including two in patients with neurofibromatosis. One additional tumor in a patient with neurofibromatosis lacked psammoma bodies but elaborated somatostatin. Eight additional tumors in nonneurofibromatosis patients produced solely somatostatin. Duodenal carcinoids often elaborate more than one polypeptide hormone; those in the ampulla often elaborate somatostatin and have psammoma bodies.

Goblet cell carcinoids and related tumors of the vermiform appendix.

Appendiceal carcinoids with glandular differentiation pose difficulties in classification and prediction of clinical behavior. Sixty-four such cases were divided into three histologic groups on the basis of routine and immunohistochemical stains: (1) Tubular carcinoids were small and confined to the appendix, had small amounts of intraluminal mucin with few or no goblet cells, were nonargentaffin, lacked serotonin, and were diffusely positive for glucagon. All ten with follow-up (mean, 17 months) were without metastasis. (2) Goblet cell carcinoids were confined to the appendix and mesoappendix, circumferentially surrounded the appendiceal lumen, and were often not suspected grossly. Histologically, they were often mixed with small crypt-like glands and were serotonin positive. All 22 with follow-up (mean, 19 months) were without metastasis whether or not right hemicolectomy was performed. (3) Mixed carcinoid-adenocarcinomas showed spread into the cecum or adjacent viscera at the time of diagnosis and had a large carcinomatous pattern with areas of mucinous, signet-ring, or single-file structure, in addition to goblet cell or insular carcinoid. All patients had right hemicolectomies, and all but two with follow-up died of the disease (mean, 16 months). Although a histologic spectrum exists among carcinoid tumors and certain adenocarcinomas of the appendix, it is possible to delineate three biologically distinct groups. Surgical margins should be taken of all appendices because these tumors often do not form discrete masses.

Carcinoid tumors of the duodenum. A clinicopathologic study of 99 cases.

Ninety-nine carcinoid tumors of the duodenum were studied. Seventy-seven patients were followed up for a mean period of 65 months, 20 tumors were autopsy findings, and two patients were unavailable for follow-up. Sixteen tumors (21%) produced metastases, all discovered initially; 3 patients (4%) died from metastatic disease (mean survival, 37 months postoperatively). Features associated with metastatic risk were involvement of muscularis propria, size greater than 2 cm, and the presence of mitotic figures. For 51 tumors, there was no correlation between immunohistochemical somatostatin and history of diarrhea, cholelithiasis, or diabetes mellitus (somatostatin syndrome). Five tumors were associated with Zollinger-Ellison syndrome and had immunohistochemical gastrin, but in the others there was no correlation between ulcer disease and gastrin positivity. Duodenal carcinoids are indolent, especially when small and localized to the submucosa. Immunohistochemical identification of somatostatin and gastrin has little clinical relevance.

Pancreaticoduodenectomy for periampullary cancer in patients more than 70 years of age.

BACKGROUND/AIMS: To assess the indications for and results of pancreaticoduodenectomy in patients more than 70 years old with periampullary cancer. METHODOLOGY: Thirty-four consecutive patients older than 70 years with periampullary cancer. The surgical procedure was pancreaticoduodectomy (Whipple's operation) with an extensive dissection of lymph nodes and the connective tissue in the peripancreatic region. Main outcome measures were postoperative morbidity and mortality, median and 5-year survival rates. RESULTS: Postoperative medical complications occurred in 24% and surgical complications in 53% of the patients. Four patients (12%) died in the postoperative period (within 30 days), and 3 patients (9%) died later in the postoperative course. The cumulative and age corrected 5-year survival rate for the remaining patients was 26%. Fifteen patients died of recurrence, and 7 patients of other causes. Five patients are still alive more than 5 years after surgery. In patients with noncurative operation the median survival time was 1 1/2 years, which is longer than would be expected from other palliative procedures. Apart from a moderately increased postoperative mortality the results were similar to those reported for younger patients. CONCLUSIONS: Pancreaticoduodenectomy should be considered in patients older than 70 years with resectable periampullary cancer. A 5-year survival rate of 20-35% can be obtained. Palliative resection may be indicated in patients in good general condition, as resection gives the best palliation and longer survival than other palliative methods.

[Gastric carcinoid tumor in pernicious anemia]. / Karcinoid tumor i ventriklen ved perniciøs anaemi.

A case of a 39 year-old woman with recently diagnosed PA and a GCT is reported. Recent surveys have shown that GCTs occur far more frequently in patients with chronic atrophic gastritis type A (+/- PA) than previously noted. This may be due to an improved endoscopic technique and the use of specific immunostains, such as chromogranin A, which in our case was essential in avoiding the diagnostic pitfall of an adenocarcinoma. The pathogenesis and the management of type-1 GCT are discussed.

The effect of blood-transfusions on renal allograft survival.

The relation between previous bloodtransfusions and renal allograft survival was studied retrospectively in 88 patients, who had been transplanted for the first time. The allograft survival rate was higher in the group who had received bloodtransfusion than in the group who had not. This difference was significantly greater when considering patients who had not previously been pregnant, e.g. patients without previous stimulation of the immuno system. The material shows no difference in allograft survival between previously transfused and non transfused patients, when considering age, sex or disease of kidney. In this retrospective study it is concluded that previous transfusions improved the prognosis of the transplantation. A prospective study has yet to be done, in order to enlighten the influence of various other factors on the allograft survival rate such as length of period or uraemia and of dialysis.

[Familial Mediterranean fever. Study of a Swiss child]. / Familiäres Mittelmeerfieber. Beobachtung bei einem Schweizerkind.

Familial Mediterranean fever (FMF) has been observed in a Swiss child without ethnic predisposition. The case is analyzed and the current literature briefly reviewed. Recurrent attacks of fever, accompanied by abdominal pain, colic and arthritic symptoms, and often by pleuritic pain and a transitory skin rash, are the hallmarks of FMF, which is predominantly seen in ethnic groups of the Mediterranean area, notably Sephardic Jews, Turks and Armenians. However, it rarely occurs among individuals without an ethnic predisposition. Its most ominous manifestation is amyloidosis, which leads to chronic renal failure within a matter of years. Thanks to colchicine treatment, which is now widely accepted, patients often lead normal lives, and it appears that amyloidosis can be prevented.

Toxicokinetics of cadmium in lactating and nonlactating ewes after oral and intravenous administration.

We studied the toxicokinetics of cadmium on two groups of ewes, a lactating group and a nonlactating group, after single intravenous and oral administrations of cadmium chloride using a semisimultaneous method and a three-compartment model. The nonlactating ewes showed a low cadmium bioavailability (0.12-0.22%), a large steady-state volume of distribution (23.8 +/- 5.4 liter/kg), and a low blood clearance (0.20 +/- 0.03 liter/kg/day). Their mean residence time was 113 +/- 28 days. The lactating ewes had a higher bioavailability (0.33-1.7%). Their mean residence time was close to that in nonlactating ewes despite a greater blood clearance (0.46 +/- 0.013 liter/kg/day) because the volume of distribution of cadmium in the body was larger (Vss = 48.8 +/- 10.3 liter/kg). Their cadmium clearance in milk, changing with time, remained low and could not explain their higher blood clearance. In one nonlactating ewe, a greater cadmium bioavailability (5%) increased cadmium in the body. Increased cadmium amounts could induce renal damage and shorten the mean residence time (78 days).

The soil fungus Chaetomium in the human paranasal sinuses.

Chaetomium is a soil fungus of which more than 180 species are now known. Most species cause degradation of cellulose-rich substrates, such as components in soil, straw or wood. Growth of Chaetomium globosum is often stimulated in the presence of Aspergillus fumigatus, which excretes such compounds as sugar phosphates and phospho-glyceric acid. A 73-year-old woman, with long-standing pain and secretion from her left maxillary sinus, was admitted to hospital where an infundibulectomy was performed. Histological examination showed necrotic material with hyphae of A. fumigatus and perithecia of Chaetomium sp. The latter fungus is rarely pathogenic to man.

Screening for dysplasia and TP53 mutations in closed rectal stumps of patients with ulcerative colitis or Crohn disease.

BACKGROUND: Patients who undergo colectomy due to intractable chronic inflammatory bowel disease (IBD) may keep a closed rectal stump for several years, which may be at increased risk of malignant transformation owing to residual inflammatory activity. We examined a hospital series of patients with ulcerative colitis or Crohn colitis to describe the clinical, endoscopical and histological features of the closed rectal stump and to screen for dysplasia and mutations in the TP53 tumour suppressor gene. METHODS: During rigid proctoscopy, rectal mucosal biopsy specimens and rectal lavage fluid were collected from 42 patients. Biopsy specimens were examined histologically, and genomic DNA extracted from frozen biopsies and lavage fluid was analysed for mutations in TP53 exons 4-9. RESULTS: The median disease duration was 8.5 years (range 1.3-34 years). No endoscopic or histological signs of dysplasia or carcinoma were seen and no mutations in the TP53 gene were detected in any biopsy or lavage fluid specimens. Histological moderate to severe mucosal inflammation was present in 78% (33/42) of the patients, however, and rectal stump involution was noted in 43% (18/42). CONCLUSION: No signs of malignancy or premalignant degeneration were detected in this prospective series of IBD patients with a closed rectal stump. Although this is reassuring for patients, the presence of moderate to severe inflammation in the majority of rectal stumps indicates a role for adjuvant molecular markers to improve colorectal cancer surveillance on this subgroup of IBD patients.