Primary retroperitoneal mucinous cystadenoma with sarcoma-like mural nodule : a case report and review of the literature.

Primary retroperitoneal cystadenomas are extremely rare. This is the first report in literature to describe a primary retroperitoneal cystadenoma with a sarcoma-like mural nodule. A 45-year-old woman complained of a left-sided abdominal mass. A computed tomography scan revealed a cystic mass with a mural nodule, which seemed to originate from the tail of the pancreas. At laparotomy the cyst was not adhered to the pancreas but localized retroperitoneally. Histologic examination showed a mucinous cystadenoma with only foci of borderline malignancy with a mural "sarcoma-like" nodule. In view of the surgical and histopathological findings, the mucinous cystadenoma was regarded as primary retroperitoneal. This case demonstrates that in the era of radiological preoperative refinement, pathological diagnosis remains of utmost importance, especially for rare cases.

[Diversity of complaints in manifesting carcinoma of the gallbladder]. / Diversiteit in klachten bij manifestatie van het galblaascarcinoom.

A man of 47 years with hypercholesterolaemia had no complaints but the family doctor suspected cholecystolithiasis because of abnormal results of the haematological study. Ultrasonography of the abdomen revealed a polyp in the gallbladder. The patient underwent laparoscopic cholecystectomy. Pathological examination revealed that the polyp was a carcinoma. No evidence for a recurrence was found during a return visit after 2 years. A woman of 74 years was admitted to the hospital due to persistent rectal bleeding. She had fever, loss of appetite, nausea and weight loss. A bleeding duodenal ulcer was identified during gastroduodenoscopy. Laparotomy was performed due to haemodynamic instability. During the operation an abnormal gallbladder was found with infiltration in and perforation of the duodenum. The gallbladder was resected and the perforation of the duodenum was sutured. Pathological examination revealed carcinoma of the gallbladder. A palliative policy was adhered to; the patient died 1 month later. Carcinoma ofthe gallbladder is an uncommon but highly fatal malignancy. Several risk factors have been identified and treatment is primarily surgical.

[Virilisation due to an ovarian mucinous cystadenoma]. / Virilisatie door een ovarieel mucineus cystadenoom.

An 82-year-old postmenopausal woman presented with severe clinical hyperandrogenism related to testosterone overproduction, possibly as a result of a mucinous cystadenoma. The cystadenoma was successfully removed in toto. The patient was discharged in good health. Plasma testosterone levels normalised 6 weeks after surgery. Ovarian mucinous cystadenomas are a rare cause ofhyperandrogenism.

Fever and high lactate dehydrogenase in HIV-positive patients from the Antilles and Surinam: histoplasmosis?

We describe four cases of HIV-positive patients, two from Surinam, one from the Dutch Antilles and one from Nigeria, who presented with a febrile illness and a high lactate dehydrogenase plasma level. In all four, the diagnosis of disseminated histoplasmosis was made, in three of them by liver biopsy. Two patients had retinal abnormalities compatible with a systemic fungal infection. Three patients were treated successfully with antifungal agents. One patient died. Between 2000 and 2006, only 14 patients with HIV have been found to have histoplasmosis in the Netherlands. Although histoplasmosis is not endemic in the Netherlands, physicians are more likely to see cases because of a growing number of HIV -positive immigrants from endemic regions.

MUC4 is increased in high grade intraepithelial neoplasia in Barrett's oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio.

BACKGROUND: Patients with Barrett's oesophagus (BO) are at risk of oesophageal adenocarcinoma. Because the pattern of mucosal mucins changes during neoplastic progression, it may serve as a marker of intraepithelial neoplasia. AIMS: To determine the expression pattern of mucins in neoplastic BO epithelium (high grade dysplasia) and correlate it with the expression of apoptosis markers Bax and Bcl-2. METHODS: Thirty seven patients with BO were studied: 16 without intraepithelial neoplasia, six with high grade intraepithelial neoplasia (HGN), and 15 with infiltrating adenocarcinoma. Biopsies were obtained from squamous epithelium, Barrett's epithelium, and (when present) foci of suspected HGN or adenocarcinoma. MUC1-4, MUC5AC, MUC5B, MUC6, Bax, and Bcl-2 mRNA were determined by semiquantitative RT-PCR. MUC2, MUC5AC, and MUC6 protein was determined by immunoblotting. RESULTS: Mucin expression varied between neoplastic progression stages in BO. Mucin mRNA levels were low in squamous epithelium, except for MUC4, and were at least four times higher in BO and HGN (p<0.001), but less so in adenocarcinoma. MUC4 expression was significantly lower in BO than in normal squamous epithelium, whereas in HGN and adenocarcinoma, levels were significantly higher than in BO (p = 0.037). The Bax:Bcl-2 ratio was increased in HGN compared with BO (p = 0.04). MUC2, MUC5AC, and MUC6 protein values correlated with mRNA data. CONCLUSIONS: Mucin expression varies during the development of oesophageal adenocarcinoma in BO. MUC4 could serve as a tumour marker in this process. In contrast to animal studies, upregulation of MUC4 in HGN is associated with increased apoptosis, suggesting that MUC4 plays a minor role in apoptosis regulation in BO.

Surveillance in Barrett's oesophagus: a critical reappraisal.

BACKGROUND: Current recommendations are for endoscopic surveillance of patients with Barrett's oesophagus to detect dysplasia and to diagnose carcinoma at an early and possibly treatable stage. However, observations suggest that these current practice guidelines are thwarted by many factors often not taken into account. These observations stem from general surveillance aspects as well from specific data on Barrett's oesophagus. This review therefore aims at discussing data on the current surveillance strategy in conjunction with general surveillance aspects relevant for their interpretation. METHODS: Literature survey of published articles. RESULTS: A critical reappraisal of the literature shows that the current surveillance strategy is hampered by multiple problems with the marker dysplasia, cost-ineffectiveness, an overrated cancer risk and an astonishing lack of prospective, randomized data showing a clear benefit in terms of a greater life expectancy. Moreover, the decisive study is unlikely ever to be performed because of the large number of patients needed and the required length of follow-up. As a result, protocols are being carried out that have never been critically tested prior to large-scale clinical implementation. CONCLUSIONS: Although these findings should not lead to therapeutic nihilism, the data raise the issue of whether or not surveillance protocols should be restricted to specialized referral centres with particular research efforts aimed at improving existing and developing new techniques that lack most of the described pitfalls and problems. Since it is foreseen that matters will not change rapidly in the (near) future, the clinician has no other choice than to rely on individually tailored arguments to survey taking into account for example family history, age and anxiety about potential long-term effects.

Disappearance of a mucosa-associated lymphoid tissue (MALT) lymphoma of the urinary bladder after treatment for Helicobacter pylori.

A59-yr old man presented with macroscopic hematuria. A non-Hodgkin's lymphoma of the MALT type of the urinary bladder, stage I A-E, was diagnosed. Radiotherapy was advised, but the patient refused this kind of treatment. Because of the known relationship of a gastric MALT lymphoma and Helicobacter pylori, the patient was treated with HP eradication therapy. Afterwards the lymphoma disappeared. The patient is 3 yr later in a persistent complete remission. This is the first known case of the disappearance of a MALT lymphoma of the urinary bladder after treatment with HP eradication therapy.

[Care for body materials obtained from autopsy]. / Zorgvuldigheid bij de omgang met lichaamsmateriaal verkregen bij obducties.

During every autopsy, small tissue samples are taken from each organ for microscopic examination. Organs or part of organs are retained for a longer period if (a) the organ concerned is so small that the entire organ is needed for the microscopic examination; (b) the organ exhibits complicated abnormalities which can only be diagnosed following fixation or a special treatment; (c) the organ must be fixed before the examination can take place, for example, the brain. This means that the corpse is not buried or cremated in its entirety. Next of kin are not always aware of this procedure even if they have given their consent for an autopsy. Changes within society, especially the handling of aborted foetal material and foetal material from intra-uterine deaths, require new agreements and rules for the retention of organs. Next of kin must be able to have confidence in the provision of information and the careful management of body material retained during autopsies.

Lack of cyclin D1 overexpression in gastric carcinogenesis.

AIMS: Cyclin D1 overexpression was examined in early gastric carcinomas and precursor lesions with the following aims; (1) to assess the chronology of cyclin D1 overexpression in various stages of gastric carcinogenesis, (2) to correlate cyclin D1 overexpression with the Lauren type, the grade of differentiation and the type of growth pattern of the tumours and (3) to correlate cyclin D1 overexpression with clinical parameters, in particular lymph node metastasis and overall prognosis. METHODS AND RESULTS: Forty-five paraffin-embedded gastrectomy specimens from early carcinomas were examined for the presence of various precursor lesions. The Lauren type, the grade of differentiation and the type of growth pattern were reassessed for all early carcinomas. Cyclin D1 overexpression was examined using the monoclonal antibody DCS-6. Cyclin D1 overexpression was absent from all precursor lesions. Ten early carcinomas (22%) were cyclin D1 positive without significant differences when stratified according to Lauren type, grade of differentiation, type of growth pattern or lymph node status. Univariate analysis failed to show a significant difference in 5-year surival rate between cyclin D1 positive and negative early carcinomas (90% vs. 94%). CONCLUSIONS: Cyclin D1 protein overexpression does not play a role in the progression from normal to neoplastic gastric mucosa and does not discriminate between intestinal and diffuse type early gastric carcinomas of Caucasian origin. Moreover, mechanisms other than cyclin D1 protein overexpression underlie the reported difference in biological behaviour of early gastric carcinomas with different types of growth pattern. Finally, although it appears that cyclin D1 does not have prognostic significance, studies on larger numbers, including advanced carcinomas, are warranted.

[Cervical smears unsuitable for exclusion of cervical carcinoma]. / Cervixuitstrijkje ongeschikt voor het uitsluiten van cervixcarcinoom.

In women with contact bleeding or vaginal discharge, cervical smears are often made to exclude the possibility of cervical carcinoma. During the past ten years, several women sued pathologists for failure to diagnose cervical cancer because of false-negative results entailing a diagnostic delay of years. This, however, is unjustifiable: clinicians have to consider the aim of performing a test and always have to interpret the outcome within the clinical context. If the indication for testing is to exclude cervical cancer with enough certainty, a false-negative rate possibly as high as 45% makes the smear definitely unsuitable for this aim.

Classification of gastric carcinoma using the Goseki system provides prognostic information additional to TNM staging.

BACKGROUND: Due to the high variability of the epidemiology, genetics, morphology, and biologic behavior of gastric carcinoma, many classification systems are in use, e.g., the World Health Organization (WHO) classification; tumor differentiation; the criteria of Ming, Mulligan, and Laurén; and the recently introduced Goseki classification. In the authors' opinion, the TNM staging is the most valuable classification system, with a prognostic value for survival. METHODS: To assess the reproducibility and usefulness of these systems in clinical practice, material from 285 gastric carcinoma patients entered in the Dutch Gastric Cancer Trial was analyzed by a panel of 5 experienced gastrointestinal pathologists. The presence of eosinophilic and lymphocytic infiltrates was analyzed in addition to the TNM staging. RESULTS: Of the analyzed classification systems, only TNM stage, tumor differentiation, eosinophilic infiltrate, and the Goseki system contained information associated with the survival of patients with gastric carcinoma. The reproducibility was perfect for tumor differentiation (Kappa 1.00), nearly perfect for the WHO and Goseki classifications (Kappa 0.86 and 0.87, respectively), reasonably good for Laurén and lymphocytic infiltrate (Kappa 0.70), and reasonably good for eosinophilic infiltrate (Kappa 0.42). CONCLUSIONS: Of all these systems, the Goseki classification was the only system with prognostic value that is additional to TNM staging.

Loss of E-cadherin expression in early gastric cancer.

AIMS: Reduction or loss of E-cadherin expression was examined in early gastric carcinomas and precursor lesions with the following aims: (1) to assess overall E-cadherin expression in various stages of gastric carcinogenesis; (2) to correlate E-cadherin expression with the Lauren type, the grade of differentiation and the type of growth pattern of the tumours; and (3) to correlate E-cadherin expression with lymph node metastasis and overall prognosis. METHODS AND RESULTS: Forty-five paraffin-embedded gastrectomy specimens from early carcinomas were examined for the presence of various precursor lesions. The Lauren type, the grade of differentiation and the type of growth pattern were reassessed for all early carcinomas. E-cadherin expression was examined using antibody HECD-1. Whereas E-cadherin was strongly and evenly expressed in the gastric foveolar epithelium, intestinal metaplasia and early gastric carcinomas showed a lower expression. A significant difference in E-cadherin expression was found between the Lauren types (P < 0.0001). Moreover, an inverse correlation was found between E-cadherin expression and histological grade (P < 0.0001). Neither a difference in E-cadherin expression between the various growth types nor an association with lymph node metastasis and overall prognosis was found. CONCLUSIONS: The Lauren types differ in E-cadherin expression, although reduced E-cadherin expression in all probability rather reflects poor differentiation than a diffuse growth pattern 'genotype'. Moreover, E-cadherin expression does not underlie the difference in biological behaviour of early carcinomas with different types of growth pattern. Finally, E-cadherin expression is not associated with lymph node status and 5-year survival rate, at least not in early gastric carcinomas.

Sickle cell-like crisis and bone marrow necrosis associated with parvovirus B19 infection and heterozygosity for haemoglobins S and E.

In the literature, heterozygosity for haemoglobins S and E is known as a clinically benign condition. Nevertheless, we present a case of double heterozygosity manifesting as an infarctive sickle cell-like crisis with acute chest syndrome and reversible bone marrow necrosis. Importantly, these complications were associated with serologically documented parvovirus B19 infection. Reviewing the literature, this case emphasizes a specific role of parvovirus B19 as a precipitating cause. Furthermore, it demonstrates how important the consideration of haemoglobin disorders can be even outside of the historically known areas.

Molecular alterations in early gastric carcinomas. No apparent correlation with Helicobacter pylori status.

Data on the differences in molecular profile between H pylori-positive and H pylori-negative early gastric carcinomas, if any, are almost nonexistent. We therefore investigated whether molecular differences can be observed between H pylori-positive and H pylori-negative early gastric carcinomas. Forty-five early gastric carcinomas were analyzed for alterations in certain oncogenes (ras, MDM2, c-erbB-2, cyclin D1), the p53 tumor suppressor gene, and the e-cadherin gene. Of these 28 carcinomas were H pylori-positive, and 17 were H pylori-negative. No significant differences were found in the groups irrespective of Lauren type; ras (0% vs 0%), MDM2 (0% vs 0%), c-erbB-2 (0% vs 0%), cyclin D1 (18% vs 29%), p53 (68% vs 47%), and e-cadherin (46% vs 41%). Helicobacter pylori-positive and H pylori-negative early gastric carcinomas do not differ in molecular profile. Although they may prove different when tested for other abnormalities, our findings suggest that the acquisition of molecular alterations occurs via an H pylori independent pathway.

p21(Waf1/Cip1) expression and the p53/MDM2 feedback loop in gastric carcinogenesis.

Data are non-existent regarding coincidental alterations in the expression of p53 and its downstream target genes MDM2 and p21(Waf1/Cip1) in gastric carcinogenesis. An immunohistochemical study was therefore performed to examine the interrelationships of p53, MDM2, and p21(Waf1/Cip1) expression in a series of Caucasian early gastric carcinomas and precursor lesions. In normal gastric mucosa, chronic gastritis, and intestinal metaplasia, the surface cells expressed p21(Waf1/Cip1) in the absence of detectable nuclear p53 and MDM2 protein. Nuclear p53 protein accumulation was found in 60 per cent of the carcinomas, with significant differences in staining characteristics between the Lauren types in the absence of detectable MDM2 protein ( p< 0.005). Nearly 80 per cent of the carcinomas expressed p21(Waf1/Cip1), irrespective of Lauren type. Stratification of the carcinomas according to histological grade and growth pattern did not result in significant differences in p53 and p21(Waf1/Cip1) expression. Finally, no significant correlation was found between overall p53 and p21(Waf1/Cip1) expression in early gastric carcinomas. It is concluded that p21(Waf1/Cip1) expression in the non-neoplastic mucosa most likely relates to cell senescence and/or terminal differentiation, perhaps even in a p53-independent manner. In view of p53/MDM2 homeostasis, the differences in p53 staining characteristics between intestinal and diffuse-type carcinomas probably result, at least in part, from a difference in the prevalence of p53 gene mutations. Moreover, p53-independent induction of p21(Waf1/Cip1) expression apparently occurs in a considerable proportion of early carcinomas. Finally, in contrast to other carcinomas, p21(Waf1/Cip1) expression is not significantly correlated with histological grade in gastric carcinomas, suggesting possible defects downstream of p21(Waf1/Cip1) as an underlying cause for this apparent discrepancy.

The prognostic significance of p53 expression for survival and local control in rectal carcinoma treated with surgery and postoperative radiotherapy.

PURPOSE: To investigate whether p53 immunoreactivity is a prognostic factor for survival and pelvic control in rectal carcinoma treated with surgery and postoperative radiotherapy. METHODS AND MATERIALS: From 1981 through 1989, 146 patients with rectal carcinoma received postoperative radiotherapy and were followed for at least 5 years or until death. The specimens of 123 of these 146 patients could be retrieved and examined immunohistochemically for p53 expression. The prognostic value for survival and pelvic control of p53 expression and other patient and treatment factors was examined by univariate and multivariate analyses. RESULTS: p53 expression has no prognostic significance for overall survival in this group of 123 patients. The only prognostic factor for survival in this material is tumor stage (p < 0.01). The actuarial pelvic recurrence rates of p53- and p53+ cases are different in favor of the p53- ones. In the univariate analysis this difference is significant (p = 0.05). However, in the multivariate analysis the influence of p53 expression, additional to stage, becomes nonsignificant (p = 0.10). This indicates that p53 expression is not a strong independent prognostic factor for pelvic recurrence. In the multivariate analysis stage turns out to be the only predictor of pelvic recurrence (p = 0.03). When only recurrences inside the radiation field are considered, there is no difference between p53+ and p53-cases. CONCLUSION: Based on this material, we have found no convincing evidence that p53 expression is an important predictor of survival or local control in rectal cancer treated with surgery and postoperative radiotherapy. We have found no evidence that possible differences in radiosensitivity between p53+ and p53- tumors have clinical significance for this group of patients.

No evidence for c-erbB-2 overexpression in gastric carcinogenesis.

AIMS: Conflicting data on c-erbB-2 overexpression in gastric carcinomas can be found in the literature with regard to overall prevalence, prognostic significance and the histological type according to Lauren. The majority of these studies have focused on advanced gastric carcinomas whereas data on c-erbB-2 overexpression in early gastric carcinomas, especially of Caucasian origin, are relatively sparse. We therefore examined a series of Caucasian early gastric carcinomas to assess overall c-erbB-2 overexpression and to correlate c-erbB-2 overexpression, if any, with the type of growth pattern and the Lauren type. METHODS AND RESULTS: Forty-five paraffin-embedded gastrectomy specimens from early carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia and dysplasia. The Lauren type and the type of growth pattern were reassessed for all early carcinomas. c-erbB-2 overexpression was assessed with monoclonal antibody 3B5 and polyclonal antibody A485. Complete absence of c-erbB-2 overexpression was observed in chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. Moreover, c-erbB-2 overexpression was found absent in both intestinal-type (n = 20) and diffuse-type early gastric carcinomas (n = 25), irrespective of growth type. CONCLUSIONS: c-erbB-2 overexpression does not play a role in the progression from normal to neoplastic gastric mucosa and should be considered as a late event in gastric carcinogenesis. Moreover, c-erbB-2 overexpression does not discriminate between intestinal and diffuse type early gastric carcinomas of Caucasian origin. Finally, it appears that mechanisms other than c-erbB-2 overexpression underlie the reported differences in biological behaviour of early gastric carcinomas with different types of growth pattern.

No evidence for functional inactivation of wild-type p53 protein by MDM2 overexpression in gastric carcinogenesis.

Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result from binding to overexpressed MDM2 protein. While these two mechanisms of p53 inactivation are considered to be mutually exclusive, no data exist as to whether MDM2 overexpression occurs during gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogenesis. Forty-five paraffin-embedded gastrectomy specimens from early gastric carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. The Lauren type was reassessed for all early carcinomas. p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal antibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype. In gastric dysplasia (one mild, two moderate, one severe), only severe dysplasia was p53-positive. Intestinal-type (n = 20) and diffuse-type early gastric carcinoma (n = 25) were p53-positive in 70 and 52 per cent of the cases, respectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cases. In conclusion, it appears that functional inactivation of wild-type p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis.

Gastric lymphomas compared with lymph node lymphomas in a population-based registry differ in stage distribution and dissemination patterns but not in patient survival.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) originating in mucosa-associated lymphoid tissue (MALT) is supposed to have different clinical behavior from lymph node NHL. To test this hypothesis, the authors compared data of gastric NHL patients with lymph node NHL patients in a population-based registry for differences in clinical presentation and prognosis. METHODS: Data from 1981-1989 on patients with primary gastric NHL (n = 109) and patients with primary lymph node NHL (n = 658) were retrieved from a Dutch population-based NHL registry. Patients were compared for stage distribution, involved sites, and survival. The prognostic value of grading lymphomas according to the malignancy grades of the Working Formulation for Clinical Usage was compared with the value of grading MALT NHLs as either low grade or high grade malignancies. RESULTS: Patients with gastric NHL presented more often with localized disease. Stage IV patients had a higher rate of dissemination to other non-lymph node sites but less frequent localization in the bone marrow. The restricted pattern of dissemination was reflected in a significantly lower recurrence rate for gastric NHL. Gastric NHL patients had significantly better disease free survival than lymph node NHL patients (80% and 44% at 5 years, respectively; P < 0.001). In contrast, overall survival did not significantly differ between the two groups, and it appeared to depend on disease stage. Grading MALT lymphoma as either low grade (26%) or high grade (70%) malignancies did not provide better prognostic information than grading according to the Working Formulation for Clinical Usage (low 8%, intermediate 75%, high 9%). CONCLUSIONS: Primary gastric NHL shows a restricted dissemination pattern, which gives support to the MALT lymphoma concept. Although this might explain the superior disease free survival observed for gastric NHL patients, it does not translate into better overall survival for these patients.