Mutations of the DPC4/Smad4 gene in biliary tract carcinoma.

A candidate tumor suppressor gene, DPC4, located at 18q21.1, has recently been shown to be inactivated in half of pancreatic adenocarcinomas. The close developmental relationship of the pancreas and biliary tract prompted us to determine the role of DPC4 in the multistep carcinogenesis of biliary tract carcinoma. A search for mutations in the genomic sequence of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational polymorphism analysis. Five of 32 (16%) primary biliary tract carcinomas had point mutations in the DPC4 sequence. Interestingly, inactivation of DPC4 was especially common in carcinomas originating from the common bile duct (four of eight specimens analyzed), suggesting an important role for DPC4 in the development of this subtype of biliary tract tumor.

Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.

PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Monoclonal antibodies against inhibin represent key markers of adult granulosa cell tumors of the ovary even in their metastases. A report of three cases with late metastasis, being previously misinterpreted as hemangiopericytoma.

Antibodies against human inhibin, a peptide hormone produced by ovarian granulosa cells to inhibit FSH, are widely applied to determine serum inhibin levels. Recently, they were, however, proved also to stain follicle cells in ovarian tissue by immunoreactions in histological sections. The commercially available inhibin antibody produced by Serotec, applied to sections of paraffin blocks, stained follicle epithelia in 6/6 samples of ovarian tissue from females under the age of 40 recruited from the archives. Adult granulosa cell tumor tissue samples from primary tumors of the ovary showed positive reaction in 6/6 cases. No positive reaction was found in staining tissues from hemangiopericytomas from males (0/3), leiomyomas, leiomyosarcomas, and a malignant melanoma (0/5), serving as negative controls. No positive reactions could be observed in tumor cells of 10 ovarian carcinomas, whereas in two of these cases single cells of the specialized ovarian stroma stained positively with inhibin. Positive immunostainings were revealed in three late metastases (two within the liver) from granulosa cell tumors in females, primarily misinterpreted as hemangiopericytomas or leiomyosarcomas, because the previously resected primaries of the ovary were not known at the time of liver surgery. The recognition of granulosa cell tumors, especially the distinction of the sarcomatoid growth type from soft tissue tumors, may be difficult, even if immunostaining for intermediate filaments are applied. Immunostaining by antibodies against inhibin, which can be applied reliably in histopathology, may therefore provide a useful tool to distinguish between granulosa cell tumors and genuine soft tissue tumors. This is also of clinical importance, because treatment of the former by cisplatin-based polychemotherapy and antisex hormone therapy proved to be helpful. Furthermore, the inhibin antibody can be used as an early serum marker for detecting tumor recurrence months before clinical evidence.

Allogeneic liver transplantation for hepatic veno-occlusive disease after bone marrow transplantation--clinical and immunological considerations.

Veno-occlusive disease (VOD) is a frequent complication early after bone marrow transplantation. In cases of severe liver failure treatment by allogeneic liver transplantation is possible. We report the clinical and immunological course of a patient after bone marrow transplantation for AML and subsequent allogeneic liver transplantation for severe hepatic VOD. After liver transplantation the patient recovered well clinically. Early after liver transplantation he had large numbers of liver donor T and NK lymphocytes in his circulation. He had no liver graft rejection, but he developed mild acute GVHD which was caused by liver graft-derived T lymphocytes. Two years after transplantation he had persistent microchimerism with donor liver cells detectable in his bone marrow. Now 36 months after transplantation, the patient has no evidence of recurrent leukemia, stable liver function, and no signs of graft-versus-host disease or bone marrow dysfunction.

Comparison of bone marrow and hematologic findings in patients with human immunodeficiency virus infection and those with myelodysplastic syndromes and infectious diseases.

The histologic, hematologic, and morphometric findings of 40 patients positive for the human immunodeficiency virus (HIV) were compared statistically with those of 40 patients with primary myelodysplastic syndromes (MDS) and those of 32 HIV-negative patients with infectious diseases. The severity of anemia and the abnormalities of erythropoiesis in the group of HIV patients were less pronounced than in the group with MDS; megakaryopoiesis showed similarities only with the group of patients with infectious diseases, and characteristics of dysplasia were not observed. Granulopoiesis in MDS showed an increase of blasts in several cases; this was not found in any biopsy specimen from the HIV group. In addition, a statistically significant increase of monocyte-like cells and giant bands could be observed in the bone marrow of the HIV patients. The peripheral blood findings and bone marrow picture in the series of our HIV patients appeared to be related mainly to the influence of opportunistic infections, although a direct effect of the HIV itself could not be excluded.

Mycobacterium genavense. Autopsy findings in three patients.

The authors report on the pathologic findings in three cases of disseminated infection with Mycobacterium genavense, a recently described nontuberculous mycobacterium, in human immunodeficiency virus (HIV)-I-positive patients. The mycobacterium was identified by amplification of a 16S rDNA gene fragment and subsequent sequence determination. The organs mainly involved were the small intestine, spleen, liver, and lymph nodes. In contrast, lungs, myocardium, and kidneys were not involved, or only minimally involved, in this generalizing disease. Histopathologically, infection with Mycobacterium genavense in HIV-positive patients was mostly characterized by masses of foamy histiocytes and, depending on the immunologic reactivity of the host, by ill-formed granulomas, rarely with small foci of necrosis. The pathologic findings and clinical features were similar to those presented by patients who had generalized infection with Mycobacterium avium-intracellulare complex. To obtain more precise information about the specific course of infection with Mycobacterium genavense, scrupulous microbiologic investigations, including molecular biologic techniques, are necessary in cases with mycobacterial infections.

Ovarian-like stroma in an invasive mucinous cystadenocarcinoma of the pancreas positive for inhibin. A hint concerning its possible histogenesis.

A female patient with a mucinous cystadenocarcinoma originating from a mucinous cystadenoma of the pancreas is presented. The cystic tumour was diagnosed 3 years before and was treated with interventional external and internal surgical drainage before radical resection was accomplished by left hemipancreatectomy. Histology showed simultaneous occurrence of mildly dysplastic and invasive malignant epithelium. Immunohistology revealed inhibin-positive cells in the ovarianlike stroma of the tumour. The demonstration of ovarian-like stroma positive for inhibin suggests that this could be a hamartoma with dispersed sex-cord stroma, which would explain the predominance of the female gender in mucinous cystic tumours of the pancreas.

Lymphadenectomy in gastric carcinoma. A prospective and prognostic study.

In 193 gastric resections for adenocarcinoma, lymphadenectomy was prospectively evaluated to quantify the number of lymph nodes and to identify prognostic factors. Overall, 7112 nodes (median, 36.8 per patient) were resected with 27.2% showing metastases. Most nodes were found in the perigastric region. The histologic type and site of the tumor did not influence the number of invaded nodes, but tumor stage and quality of the resection (curative/palliative) did. By multivariate analysis the tumor stage, curative vs palliative resections, and the number of metastatic lymph nodes in curative resections were independent prognostic factors. Patients with less than six metastatic nodes showed a survival not significantly different from that of patients with normal nodes. These patients may be well treated by surgery alone, but the other patients may require multimodal therapy to improve their prognosis.

Favourable prognosis of cystadeno- over adenocarcinoma of the pancreas after curative resection.

This report details nine patients after curative surgical resection of histologically proven mucinous cystadenocarcinoma of the pancreas and compares the prognosis with ductal adenocarcinomas. Cystadenocarcinomas represented 2.1% (10/ 466) of a total of 466 patients who underwent surgical exploration and 5.5%, of all curatively resected carcinomas of the exocrine pancreas at Hanover Medical School from 1971 to 1994. Forty percent of adenocarcinomas and 90% of cystadenocarcinomas were resectable. A curative R0 resection was possible in all patients with cystadenocarcinoma and 85 % with adenocarcinoma. Six of the patients with cystadenocarcinoma were female and three were male. Their median age was 54 +/- 12 years (range: 44 to 81 years). Four cystic neoplasms were located in the head, one in the head and body, three in the tail, and one in the body and tail of the pancreas. There was no hospital mortality in this group. The prognosis after resection of cystadenocarcinomas was significantly better compared to ductal adenocarcinomas of the pancreas. The Kaplan-Meier survival was 89% vs 52% after 1 year, and 56% vs 13% at 5 years. Our results indicate the favourable prognosis of cystadeno- over ductal adenocarcinomas of the pancreas in a cohort of patients with curative tumour resection.

Two chromosomally different cell populations in a partly cellular congenital mesoblastic nephroma.

The conventional fibromatous and cellular areas of a congenital mesoblastic nephroma were studied using electron microscopy, and in vitro and cytogenetic methods. In light- and electron-microscopic studies, as well as in cell cultures, mature and immature mesenchymal cell types that corresponded to the fibromatous and cellular areas of the tumor were found. The conventional fibromatous portion of the tumor showed a normal chromosomal pattern, while the cellular, pleomorphic tumor area was characterized by an aneuploid clone with 54 chromosomes. The value of cytogenetic analysis of congenital mesenchymal renal tumors as a possible diagnostic tool in histologically questionable cases is discussed.

Medial meniscus replacement by a tendon autograft. Experiments in sheep.

In 20 skeletally mature female merino sheep, divided into four groups, we performed total medial meniscectomy, removal of the middle third of the patellar tendon, and tenotomy of the calcaneal tendon of the right hind leg. Group I (control) had no additional procedures. In the other three groups the medial meniscus was replaced by the middle third of the patellar tendon from the ipsilateral knee. The animals were killed at three (group II), six (group III), or 12 months (group IV) and the tendon-meniscus examined macroscopically, by light and scanning electron microscopy, and biomechanically. Remodelling of the tissue had taken place by 12 months but the failure stress and tensile modulus for the tendon-meniscus were lower than for the normal meniscus. Our evidence suggests that, in sheep, replacement of a meniscus by a tendon autograft may decrease the severity of the degenerative changes that occur after meniscectomy.

Beta 1 integrin expression in adenocarcinoma of Barrett's esophagus.

BACKGROUND/AIMS: In vitro and in vivo studies did not show that beta 1 integrin expression is associated with malignant transformation or that it is of prognostic value in some malignant tumors. There are no data on the expression or prognostic value of beta 1 integrins in adenocarcinoma of Barrett's esophagus. METHODOLOGY: We assessed the expression pattern and the prognostic impact of beta 1 integrins in paraffin-embedded specimens of 41 patients with adenocarcinoma of Barrett's esophagus by immunochemistry. At the time of investigation, neither histomorphological parameters nor the survival time were known. RESULTS: There was no correlation between histomorphological parameters and the expression of beta 1 integrins. The expression of beta 1 integrins had no influence on long- term survival. There was a relationship between the prognosis and the following histopathological parameters: pT, pN and pM category, the UICC stage, the presence of lymphangiosis, and the DNA content of the tumor cells. CONCLUSIONS: The preliminary results obtained in this study did not show that the expression of beta 1 integrins was of prognostic value in patients with adenocarcinoma of Barrett's esophagus. Further studies in a larger number of patients are required to confirm the results obtained in this investigation.

Long-term results of the use of silicone sheets after diskectomy in the temporomandibular joint: clinical, radiographic and histopathologic findings.

The aim of the present study was to evaluate the long-term results of a group of patients who had the disk of the temporomandibular joint (TMJ) removed and permanently replaced by a silicone sheet. The study group comprised 48 patients, treated in the period from 1983 to 1993. In eight patients, the implants had to be removed after an average interval of 5.6 years and they were submitted for histopathological examination. Twenty-five of the 40 patients with silastic implants in place, and five of the 8 patients who had their implants removed, were available for long-term follow-up (mean interval of 7.0 years, SD 2.8 years). Clinical function was rated according to the Helkimo Dysfunction Index and compared to the preoperative findings. Results showed decreased tenderness of muscles and joints to palpation and increased mouth opening, but no statistically significant improvement in joint function. In 4 patients, a decrease in condylar width was found, while another 4 patients presented with thickening of the condyle by appositional bone formation. Histopathology of the failed implants showed scattered fragments of silastic material and dacron fibers with accumulation of histiocytes in immediate contact with the silicone particles and phagocytozed intracellular material. T-lymphocytes were also present in the vicinity of the silicone particles.

Fatal pulmonary embolization after reaming of the femoral medullary cavity in sclerosing osteomyelitis: a case report.

Reaming of the medullary may be used in cases of sclerosing osteomyelitis (type Garré), refractory to other methods. We report a case of fatal intraoperative complication related to this procedure. An otherwise healthy young patient died during reaming using a machine-driven reamer of the femoral medullary canal due to pulmonary bone embolism. The technique and the indication for this procedure as well as the intraoperative monitoring options are discussed.

Retroperitoneal lymphangiomyoma in an infant.

Lymphangiomyomatosis (LAM) is a benign tumor-like lesion of lymphatic vessels with unknown etiology. 80 cases of LAM are presently described. So far, it appears that only women in their reproductive years seem to be affected. Here, we describe the first LAM in an 11-months-old infant with a presumably local form of LAM. This leads us to consider the possibility that this tumor-like lesion may originate from a hamartomateous malformation. The diagnosis is based on pre-operative sonography and CT, as well as on histological and immunohistochemical examination of the tumor.

[Expression of CD44 and isoforms v4, v5, v6, v7, v10--new prognostic parameters in ductal pancreatic carcinoma?]. / Expression von CD44 und seiner Isoformen v4, v5, v6, v7, v10--neue prognostische Parameter beim duktalen Pankreascarcinom?

UNLABELLED: Prognostically relevant factors based on the histological assessment of the resected pancreas are known. However, additional parameters, such as biological staging of the intrinsic malignant potentiality of the tumor, would be useful. There has been no uniform finding of a relationship between CD44 variant expression and tumor progression. METHOD: We assessed the expression pattern and prognostic impact of CD44 standard and CD44 isoforms v4, v5, v6, v7 and v10 in 40 ductal pancreatic carcinomas by immunochemistry on paraffin-embedded tumor material in patients after tumor resection. At the time of the investigation neither histomorphological parameters nor the survival time were known. RESULTS: There was no correlation between the histomorphological parameter and the expression of CD44 splice variants. CD44 splice variants v4-v10 were almost only expressed in tumor tissue. In ductal pancreatic carcinoma, patients with an overexpression of CD44 splice variants had a worse prognosis. However, because of the small number of cases this was statistically not significant. CONCLUSION: CD44 splice variants may have an influence on prognosis in ductal pancreatic carcinoma. However, further investigation on a larger number of patients is necessary to confirm these results.

[Histopathology and clinical aspects of primary myelodysplastic syndrome]. / Histopathologie und Klinik des primären myelodysplastischen Syndroms.

The histopathology of bone marrow in primary myelodysplastic syndromes (MDS) is described, with reference to the FAB classification. Variants such as hypoplastic, thrombocythemic and fibrotic MDS are recognized from their histopathology and must be incorporated in the FAB classification. The clinical significance of hypoplastic, thrombocythemic and fibrotic variants is illustrated by the survival rates and leukemic transformation in these patients. Histopathological classification according to the FAB system corresponds with cytological classification, as proven by the distribution of the subtypes, blood values, leukemic transformation rates and survival times. Finally it is even possible to elaborate a prognostic score for survival based on histological features of diagnostic biopsies, which emphasizes the importance of histopathological examination of bone marrow in MDS patients.

Benign giant-cell tumor of the patellar ligament.

We report the symptoms, clinical findings, and treatment of a patient with an extra-articular benign giant-cell tumor of the patellar ligament. Between the years 1966 and 1996 no similar case has been found to be documented by a Medline search. On palpation, a soft, mobile lesion, the size of a pigeon's egg, was felt in the lateral region of the patellar ligament. There was no set of laboratory values to determine the diagnosis. In addition, there were no typical findings in diagnostic imaging procedures and it seems that the most important fact is that the clinician is aware of this type of synovial tumor. A clear diagnosis is only possible by means of a pathological investigation. The choice of therapy for giant-cell tumors is local excision. Arthroscopy is recommended exclusively for the diagnosis and therapy of a localized intra-articular giant-cell tumor.