Herwart F. Otto

Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension

Pulmonary tumor thrombotic microangiopathy is characterized by fibrocellular intimal proliferation of small pulmonary arteries and arterioles in patients with metastastic carcinoma. Its morphologic features, including precursor lesions, were studied in 21 patients diagnosed in 630 consecutive autopsy cases with carcinoma (3.3%). Nineteen of 21 patients had adenocarcinoma and 11 of these 19 patients had gastric carcinoma. The pathogenetic events start with microscopic tumor cell embolism. Tumor emboli do not occlude affected vessels but induce both local activation of coagulation and fibrocellular intimal proliferation, which lead into stenosis or occlusion. Hemodynamically, an increase in vascular resistance results in pulmonary hypertension. In three patients, metastatic carcinoma was unknown before death, and the condition was diagnosed as pulmonary hypertension of unknown origin. Thus, pulmonary tumor thrombotic microangiopathy should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with well‐known carcinoma who develop acute or subacute cor pulmonale.

Histologic classification of thymic epithelial tumors: comparison of established classification schemes.

The object of our multicenter retrospective study was to compare the new histologic World Health Organization (WHO) classification and the classical histologic Bernatz classification in terms of interobserver agreement and prognostic importance. The influence of coexisting diseases was also analyzed using the Charlson score. We evaluated 218 patients from 5 different hospitals who were treated between 1967 and 1998. The statistical methods of analysis included Kaplan‐Meier estimates of survival curves and the application of Cox proportional hazards models to identify sets of prognostic factors for survival. Interobserver agreement was assessed by kappa coefficients. For both WHO and Bernatz classifications, interobserver agreement was good (weighted kappa > 0.87). However, the subdiversification of the “bioactive” WHO subgroup (B1, B2, B3) resulted in an interobserver agreement of only 0.49 within this group. In multivariable models, both the WHO classification and the Bernatz classification including carcinomas showed similar prognostic capabilities. The B3 type in the WHO classification and the predominantly epithelial type in the Bernatz classification had an intermediate prognostic ranking in comparison with the carcinomas and with the other subgroups. For both classifications, further simplification and subclassification into 3 subgroups led to classes with good discriminative power in respect to survival. In addition, very good interobserver agreement was observed in the simplified classifications. Comorbidity, sex, age of the patient and lymphofollicular hyperplasia had no major influence on overall survival. Both classifications showed similar prognostic power. Interobserver agreement of the type B subgroups was only moderate. By simplification of the classifications, subgroups with distinct survival could be identified.

Prognostic value of codon 918 (ATG→ACG) RET proto‐oncogene mutations in sporadic medullary thyroid carcinoma

We have determined the frequency of 918 RET proto‐oncogene mutations (ATG→ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG→ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild‐type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow‐up time. However, 918mt patients showed more aggressive development of distant metastases during follow‐up (p = 0.032, Fishers exact test) with decreased metastases‐free survival (p < 0.005, log‐rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log‐rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow‐up treatment.

Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease

Abstract Abstract. To define mediator profiles in inflamed and noninflamed areas in inflammatory bowel disease (IBD) we analyzed the expression of 35 messenger-RNAs (mRNAs) encoding cytokines, chemokines, and some related molecules in transmural gut tissues (n=138) from patients with ulcerative colitis (UC), Crohns disease (CD), and inflammatory and normal controls by real-time quantitative reverse transcription polymerase chain reaction. Using sample collectives with a comparable degree of inflammation, most parameters investigated showed similarly increased mRNA expression levels in both active UC and CD. This included proinflammatory cytokines, but also interferon (IFN) γ and several IFN-γ inducible chemokines. Only macrophage inflammatory protein (MIP)-2α mRNA was expressed at higher levels in inflamed UC vs. CD. IH revealed that MIP-2α protein was produced mainly by intestinal epithelial cells. Importantly, in histologically noninflamed/inactive IBD samples mRNAs for several mediators were significantly enhanced, accompanied by elevated levels of migration-inhibition factor related protein (MRP) 14 transcripts. CD14 positive macrophages were found especially in noninflamed/inactive UC, many of which coexpressed the RFD-7 antigen. Our results indicate a substantial overlap in cytokine/chemokine mRNA expression in UC and CD. Elevated mediator expression is evident in noninflamed/inactive areas in both diseases. Local recruitment of MRP-14 positive leukocytes might contribute to this phenomenon. In inactive UC a phenotypically altered population of macrophages expressing CD14 might play an additional role.

Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene.

The small intestinal mucosa makes up about 90% of the total surface of the gastrointestinal tract. However, adenocarcinomas arise rarely in this location. To elucidate genetic alterations underlying tumour development in the small intestine we investigated 17 sporadic adenocarcinomas. By comparative genomic hybridization recurrent gains of chromosomal material were found at chromosomes 7, 8, 13q, and 20 (5/17, each), while non-random losses were seen at 8p, 17p (4/17, each), and 18 (8/17 cases). Deletions at 5q, the location of the APC tumour suppressor gene, were seen in three cases. Microsatellite analysis with markers on chromosomal arms 1p, 5q, 8p, 17p, 18q, 19p, and 22q revealed a microsatellite instable phenotype in two cases and a high frequency of loss at 18q21-q22 (80%). Given the high incidence of 18q21-q22 deletions, we performed sequencing analysis of SMAD4, a downstream component of the TGFβ-pathway, located at 18q21. Four tumours displayed mutations in highly conserved domains of the gene indicating disruption of TGFβ-signalling. Our data reveal complex genetic alterations in sporadic small intestinal carcinomas. However, most tumours share deletions of 18q21-q22, which frequently target SMAD4. This indicates that disruption of TGFβ-signalling plays a critical role in small intestinal tumorigenesis.

β-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma

Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years. Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli. In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. A major function of APC is the downregulation of β‐catenin, a transcription‐activating protein with oncogenic potential. In an ongoing immunohistochemical study of β‐catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased β‐catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas. Sequencing of exon 3 of the β‐catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples. Our data indicate for the first time that β‐catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the β‐catenin gene may substitute biallelic APC inactivation in this tumor type. Genes Chromosomes Cancer 25:399–402, 1999.

Study of the malformation of ductal plate of the liver in Meckel syndrome and review of other syndromes presenting with this anomaly.

Meckel syndrome (MIM 249.000) is an autosomal recessive disorder with a variable spectrum of anomalies. Since the first reports of this syndrome, very broad diagnostic criteria have been proposed, but the process of defining them continues. It is probable that at least two of three manifestations, including cystic kidney dysplasia, occipital encephalocele or other anomaly of the central nervous system, and postaxial polydactyly occur in most cases. Arrest of the development of intrahepatic bile ducts at the stage of the bilaminar plate formation or ductal plate malformation is considered of high diagnostic value in Meckel syndrome, but there is no complete agreement in the literature about its occurrence. The aims of this investigation were to study the prevalence and morphologic patterns of ductal plate malformation of the liver in Meckel syndrome by evaluating the dilatation of primitive biliary structures and the increase in connective tissue of the portal tract. Archival data files from four German centers (Berlin, Freiburg, Heidelberg, Mainz) were reviewed. Liver sections of 30 well-studied fetuses with Meckel syndrome were immunostained with antibodies against cytokeratins (intermediate filaments of the cytoskeleton) and factor VIII (an endothelial cell marker) and were evaluated both qualitatively and quantitatively. Cystic kidney dysplasia, occipital encephalocele, and postaxial polydactyly were found in 100%, 90%, and 83.3% of the fetuses, respectively. Ductal plate malformation of the liver was a constant anomaly in Meckel syndrome, seen as frequently as renal lesions. We observed essentially two kinds of hepatic lesions: 23 cases showed mainly a cystic dilatation of primitive biliary structures with little portal fibrosis, while 7 cases showed mainly rings of interrupted curved lumina around a central fibrovascular axis and pronounced portal fibrosis. In these seven cases an abnormal pattern of the portal vein, with many small and closely spaced branches of the portal vein (the so-called pollard willow pattern), was also seen. With respect to other fetal developmental anomalies, no difference between the two types of lesions was found. We also provide a potentially useful comprehensive review of other genetic syndromes in which ductal plate malformations may occur.

Thymoma: A clinicopathologic study of 98 cases with special reference to three unusual cases

98 thymomas were assessed in respect to clinical manifestations, gross and histologic pathological findings and clinicopathologic correlations. 34% of patients were asymptomatic and thymoma was detected fortuitously. The most common presenting symptoms were related to myasthenia gravis, symptoms due to pressure on mediastinal structures were next in frequency. The symptom-diagnosis interval ranged from 0 to 120 months with a median of 4,5 months and was longer in invasive thymomas (median 6 months) than in noninvasive thymomas (median 2 months). 52% of thymomas were encapsulated and showed no cytologic atypia and were therefore classified as benign encapsulated thymomas. 26% showed gross invasion of peripheral structures and 3% were thymic carcinomas on histologic grounds. Histologically 55% of thymomas were epitheloid cell type, 17% spindle cell type and 20% mixed type thymomas. Epidermoid type thymoma occurred in 3% of the cases. 3 cases showed some unusual morphologic feature: one was localized intrapulmonal, another had an outspread like a mesothelioma, and the third was a basaloid carcinoma with unusual goblet cell metaplasia. In the three cases immunohistological methods were used as a diagnostic tool. The lectins UEA-I, PNA and HPA and an anti-keratin allowed the diagnosis of epithelioma (in 2 cases) and showed some more cellular and structural differentiations (in 1 case).

Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli

Patients with familial adenomatous polyposis coli (FAP) carry heterozygous mutations of the APC gene. At a young age, these patients develop multiple colorectal adenomas that consistently display a second somatic mutation in the remaining APC wild‐type allele. Inactivation of APC leads to impaired degradation of β‐catenin, thereby promoting continuous cell‐cycle progression. The role of APC inactivation in rare extracolonic tumors of FAP patients has not been characterized sufficiently. Among tissue specimen from 174 patients with known APC germ‐line mutations, we identified 8 tumors infrequently seen in FAP. To investigate the pathogenic role of APC pathway deregulation in these lesions, they were analyzed for second‐hit somatic mutations in the mutational cluster region of the APC gene. Immunohistochemistry was performed to compare the expression pattern of β‐catenin to the mutational status of the APC gene. Exon 3 of the β‐catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated β‐catenin concentration. Although CTNNB1 mutations were not observed, second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of β‐catenin. No APC mutations were seen in focal nodular hyperplasia of the liver, angiofibrolipoma, and seborrheic wart. This is the first study reporting second somatic APC mutations in FAP‐associated uterine adenocarcinoma and epidermal cysts. Furthermore, our data strengthen a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients.

Cystic lymphangioma of the small-bowel mesentery : Case report and a review of the literature

Cystic lymphangioma of the small-bowel mesentery is a rare manifestation of an intraabdominal tumor in elderly patients. We present a case of a small-bowel mesentery lymphangioma, causing fever and chills and present clinical and pathologic features. Furthermore, etiology and differential diagnosis of this tumor are discussed.