Outcome after resection of one hundred gastrointestinal stromal tumors.

AIMS: To evaluate the outcome after surgical resection in patients with gastrointestinal stromal tumors and to determine the factors influencing local tumor recurrence or distant metastatic disease after locally complete tumor resection (R0). METHODS: Outcomes of 100 patients with primary gastrointestinal stromal tumors (GIST) surgically managed between 1997 and 2006 at a single institution were reviewed. Univariate and bivariate analyses were used to determine factors affecting recurrence-free and tumor-free survival. RESULTS: All patients (n = 100) had c-kit-positive GIST. There were 17% (n = 17) very low risk, 41% (n = 41) low risk, 19% (n = 19) intermediate risk and 23% (n = 23) high risk GIST originating from the stomach, small bowel, colon and rectum. The median patient age was 68 years (range 39-92). Seventy-three percent of the patients had symptomatic local disease. Most (94%; n = 94) of them underwent R0 resections of their primary tumor. R0 resection was significantly associated with a lower tumor-related mortality rate (p = 0.0001). The patients with recurrence/metastases had significantly larger tumors (p = 0.0017) and a mitotic index higher than 5/50 HPF (p = 0.0001). Seven of 20 patients from the high-risk group and 2 of 7 patients with metastatic disease developed local recurrence or further metastatatic tumor spread following R0 resection. CONCLUSION: Surgical removal continues to be the mainstay of GIST treatment. R0 resection, tumor size and mitotic index are significant prognostic factors. Overall, more than 30% of the patients with high-risk GIST develop local recurrences and distant metastases despite R0 resection. Additional molecular pathological markers are needed to yield a more accurate tumor profile and to thus achieve a better predictability of the biological behavior of GIST.

Perivascular epithelioid cell sarcoma (malignant PEComa) of the ileum.

Epithelioid angiomyolipoma (AML) is the prototype of a heterogeneous group of lesions characterized by the presence of HMB-45 positive cells with clear cytoplasm, perivascular distribution, and combined myomelanocytic features, so-called perivascular epithelioid cells (PECs). These lesions are being increasingly referred to as PEComas. PEComas have been reported at diverse anatomic sites, but mainly in the abdominopelvic cavity and rarely in parenchymatous organs, skin, and soft tissues. Gastrointestinal (GI) PEComas are exceptionally rare, with less than 10 cases documented so far. Rare examples of PEComas with pleomorphic histology could have been misinterpreted as unusual variants of carcinoma or sarcoma. To make a contribution to the differential diagnosis of difficult-to-classify pleomorphic GI sarcomas, we report on a malignant pleomorphic neoplasm with features of PEComa involving the terminal ileum in a 63-year-old woman. Fourteen months after resection of the primary tumor, a huge abdominopelvic recurrence was successfully resected, but no distant metastases were detected. The differential diagnosis and malignancy criteria of GI PEComas will be discussed.

Infrequent mutations of the p53 gene in pulmonary carcinoid tumors.

Archival specimens of 25 pulmonary carcinoids including 15 cases of typical carcinoid, 9 atypical carcinoids, and 1 large-cell neuroendocrine carcinoma were analyzed for mutations in exons 5 to 8 of the p53 gene. Mutations were identified in 4 tumors, including 3 out of 15 (20%) typical carcinoids and the single large-cell neuroendocrine carcinoma, but none of the atypical carcinomas showed a mutation. The mutations were acquired during tumor development since they were not present in the corresponding nontumorous tissue. All mutations in the typical carcinoids, a tumor type without epidemiological link to cigarette smoking, were G to A transitions. The level of p53 protein was investigated by immunohistochemistry with the polyclonal antibody CM-1. None of the pulmonary carcinoids investigated showed a positive reaction, despite the presence of missense mutations in two cases. Negative staining of carcinoids with mutations was also observed with the monoclonal antibodies pAb1801 and DO-1. Our data suggest that point mutations of the p53 gene are infrequent in pulmonary carcinoids thus contrasting the findings in other histological types of lung cancer, in particular small-cell lung cancer. Moreover, negative immunostaining for p53 is no indicator for the absence of p53 missense mutations in typical carcinoids.

Malignant fibrous histiocytoma (MFH). A comparison of MFH in man and animals. A critical review.

This review gives information about localization and types of MFH in man and animals such as mouse, rat, cat, dog, opossum, cattle, horse and birds [e.g. mallard (a wild duck)]. Furthermore, this paper reports about cell culture dealing with MFH. The aim of this publication is to show that MFH originates from a primitive mesenchymal stem cell, fibroblastoid cell and fibroblasts. Histiocytes are, according to the literature in a small amount constituents of MFH and are reactive cells or without any meaning. In our own studies using rats [strain: Chbb: THOM (SPF)] the characteristic storiform or cartwheel pattern of tumour cells were evident. The cells were elongated, rich in endoplasmic reticulum and possessed no or very few lysosomes. The cells were predominantly fibroblasts and fibroblastoid cells. These cells were intermingled with giant cells. In other species mentioned above, the MFH showed very similar histological features. Our own results and findings obtained from the literature support our concept that the MFH represents a primitive phenotype or pleomorphic sarcoma which may differentiate in one or more directions. Histiocytes are not a neoplastic component.

Role of metabolic activation in the toxicity of S-(pentachlorobutadienyl)glutathione and S- (pentachlorobutadienyl)- l -cysteine in the isolated perfused rat kidney.

The nephrotoxicity of hexachlorobutadiene (HCBD) has been attributed to a sequence of metabolic steps initiated by conjugation of the haloalkene with glutathione in the liver. Current evidence suggests that the conjugate S-(pentachlorobutadienyl)glutathione (PCBG) thus formed is degraded in the kidney by dipeptidase(s) to the cysteinylglycinyl conjugate. Subsequent hydrolysis by γ-glutamyltranspeptidase (GGT) leads to the cysteine conjugate S- (pentachlorobutadienyl)- l -cysteine (PCBC), which is cleaved by cysteine conjugate ß-lyase to pyruvate, ammonia and a reactive thiol, which is presumed to induce nephrotoxicity and nephrocarcinogenicity. In the isolated perfused rat kidney PCBG produced concentration-dependent nephrotoxicity as indicated by the occurrence in the urine of alkaline phosphatase and GGT and by the impairment of glucose reabsorption. The nephrotoxicity of PCBG was blocked by the specific GGT inhibitor, AT-125 (L-αS,5S)-αamino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) and by aminooxyacetic aid (AOAA), an inhibitor of ß-lyase. PCBC, A presumptive intermediate in the metabolic activation of PCBG, caused a rapid onset of massive nephrotoxicity which was blocked effectively by AOAA. At 0.1 mm-PCBC the increase in biochemical parameters of nephrotoxicity was accompanied by massive tubular necrosis. It is concluded that the glutathione conjugate of HCBD is metabolized within the target organ, the kidney, to PCBC, which is activated by renal ß-lyase to a highly nephrotoxic intermediate.

Features of prostatic sarcomas in combined aspiration and punch biopsies.

Of malignant prostatic tumors, 0.1% to 0.2% are believed to be sarcomas; about 30% of these are observed in the first decade of life. We present the morphologic findings in three patients aged 55 to 70 years in whom an osteosarcoma and two leiomyosarcomas were demonstrated by combined aspiration and punch biopsies. The sarcomas clearly differed cytologically from the various forms of prostatic carcinoma. Some difficulties in the distinction of pleomorphic tumor cells of leiomyosarcomas from pleomorphic epithelial cells from the seminal vesicle may occur. One fibrosarcoma was diagnosed by punch biopsy alone in a 57-old-year patient. The incidence of sarcomas in our material was 0.17% of all malignant tumors of the prostate.

[Suture of the submucosa in large intestine anastomosis]. / Naht der Submucosa bei der Dickdarmanastomose.

A comparison of three different suture techniques on the large bowel of the same experimental animal demonstrated that careful suture alone is adequate to produce a sufficient anastomosis. The advantages of this suture technique are to provide strength to the intestinal anastomosis, less scar tissue, and fewer peritoneal adhesions. The experimental results suggest that suturing of the submucosa can be used on other intestinal areas, too.

[Radiogenic damage of the intestine--diagnosis and therapy]. / Die radiogenen Schäden des Darmes--Diagnose und Therapie.

62 patients underwent surgery for intestinal radiation injuries during the past 15 years. 34 patients had previous abdominal surgery. Preoperative investigations must clarify if there is only the radiation lesion or a recurrent process of the originally radiated tumor. Rectovaginal fistulas occurred 28 times, 19 of which could only be treated by continent colostomy. 5 patients had been curatively resected with low anastomosis. A progressive stenosis leading to an ileus symptomatology appeared in 24 patients. The injured intestinal part was resected. As intestinal radiation injuries are combined with an ischemic enteropathy, anastomosis will be extremely problematic. Thus, second-look operations are recommendable for the third and seventh postoperative day. So lethality could be decreased.

[Epidermoid cyst of the testis]. / Die Epidermoidzyste des Hodens.

This is report of a group of four patients with epidermoid cysts of the testis. The pathogenesis, symptomatology, pathology and therapy of this benign testicular tumor (or tumor like testicular lesion) in these cases, including 150 reported cases in the literature are presented and discussed.

[Opportunistic infections and HIV-associated malignancies. An evaluation of 58 autopsy cases within 10 years]. / AIDS--Opportunistische Infektionen und HIV-assoziierte maligne Erkrankungen. Eine Auswertung von 58 Sektionsfällen aus einem Zeitraum von zehn Jahren.

PATIENTS AND METHODS: Of all patients who died of HIV infection within 10 years (1. 1. 1988 to 31. 12. 1997) at the Klinikum Nürnberg 58 autopsy cases were reviewed at the Institute of Pathology of the above mentioned hospital. RESULTS: The male:female ratio was 2.1:1, the mean age being 40.5 years. Most of the patients showed an advanced stage of lymphadenopathy at the moment of death. Non-Hodgkin's lymphoma and Kaposi's sarcoma, both HIV-related malignant diseases, were diagnosed in 6/58 cases, 10.3% each. HIV-related myelodysplastic changes existed in 28/58 patients (48.3%). Twelve patients showed an HIV-associated encephalopathy (20.7%). Opportunistic infections (pneumocystis carinii, cytomegaly, toxoplasmosis, atypical mycobacteriosis) were found in 28/58 patients (48.3%). A mycosis was diagnosed in 9/58 cases (15.5%). Tuberculosis was identified in 4/58 patients (6.9%). Cirrhosis of the liver was ascertained in 8/58 patients (13.8%). 24/58 patients (41.4%) died of respiratory disorder. CONCLUSION: In the acquired immunodeficiency syndrome numerous morphological findings will be helpful in diagnosis and therapy.

Distribution of neural cell adhesion molecule (NCAM/CD56) in gastrointestinal stromal tumours and their intra-abdominal mesenchymal mimics.

BACKGROUND: The distribution and reactivity pattern of neural cell adhesion molecule (NCAM/CD56) in gastrointestinal stromal tumours (GISTs) and their mesenchymal mimics have not been investigated in the KIT era. METHODS: 275 histologically and immunohistochemically well characterised primary and metastatic intra-abdominal mesenchymal lesions were analysed by conventional immunohistochemistry, with emphasis on GIST and GI smooth muscle neoplasms. RESULTS: CD56 expression was seen in 18/21 (86%), 4/5 (80%), 26/34 (76%), and 32/168 (19%) of primary GI leiomyomas, schwannomas, leiomyosarcomas, and GISTs, respectively. Reactivity in GISTs was mostly focal. Of 6% strongly staining GISTs, 71% were either malignant clinically or assigned a high risk prognostic group. CD56 expression in GISTs varied greatly with histological type (seen in 50% and 7% of epithelioid and spindled GISTs, respectively) and anatomical site (in 33%, 10%, 1%, and 0% of rectal, gastric, small intestinal and oesophageal GISTs, respectively). A variable, but inconsistent expression was seen in miscellaneous lesions including dedifferentiated liposarcoma, abdominopelvic PEComa, myo/fibroblastic sarcoma and malignant fibrous histiocytoma. Mesenteric fibromatoses, angiosarcoma/Kaposi sarcoma, reactive tumefactive fibrogenic lesions and 12/13 primary anorectal and oesophageal melanomas were negative. CONCLUSION: Results confirmed the ubiquity and non-specificity of CD56 as a neurogenic marker. Except for a subset of epithelioid gastric and high-grade rectal GISTs, CD56 expression is rare in GISTs, contrasting with true leiomyomatous and neurogenic neoplasms. CD56 plays a limited role in the differential diagnosis of GIST. Its potential role as a marker of adverse outcome in GISTs remains to be further investigated.

Low-grade abdominopelvic sarcoma with myofibroblastic features (low-grade myofibroblastic sarcoma): clinicopathological, immunohistochemical, molecular genetic and ultrastructural study of two cases with literature review.

AIMS: Low-grade myofibroblastic sarcoma (LGMS) represents a rare soft tissue neoplasm with a predilection for the head and neck. Intra-abdominal LGMS are rare with only four unequivocal examples reported so far. Two further cases in females in their 60s and 70s are analysed here. METHODS: Immunohistochemical stains were applied on fresh-cut sections using the avidin-biotin complex method and the following antibodies: vimentin, alpha-SMA, desmin, h-caldesmon, S-100, CD117, CD34, fibronectin, HMB45, Pan-keratin, Ki-67, beta-catenin, MDM2, PDGFRalpha, PDGFRbeta and ALK-1. Genomic DNA was isolated from microdissected formalin-fixed paraffin-embedded tumour tissue and examined for KIT and PDGFRA mutations by PCR and direct sequencing of KIT and PDGFRA. Ultrastructural studies were also performed. RESULTS: The tumours arose in the mesentery and the pelvic peritoneum. Both revealed features intermediate between conventional fibrosarcoma and leiomyosarcoma with fascicles of spindled, stellated or plump cells possessing fusiform indented vesicular nuclei and pale eosinophilic cytoplasm. Mitotic activity ranged from 1 to 15 per 10 HPFs. The tumour cells strongly expressed vimentin, variably alpha-smooth muscle actin and fibronectin, but were negative for CD117, S-100, desmin, h-caldesmon, beta-catenin, ALK-1, MDM2, PDGFRalpha and PDGFRbeta. One tumour showed a weak expression of CD34. Molecular analysis revealed a wild-type KIT, exons 9, 11 and 13, and PDGFRA, exons 12 and 18. The patients developed multiple peritoneal recurrences at 5, 13 and 25 months, and 10, 19, 25 and 32 months, and were alive at 25 and 32 months, respectively. Distant metastases were not detected. CONCLUSION: Abdominopelvic LGMS follows a more aggressive clinical course characterised by a higher propensity for local recurrence, contrasting their more superficially located counterparts. LGMS may mimic a variety of benign and low-grade malignant neoplasms and might be under-recognised.

[Experiences of the Bavarian mammography screening program]. / Erfahrungen aus dem Bayerischen Mammographie-Screening-Programm.

The Bavarian Mammography Screening Program started in April 2003. A detailed analysis of the consistency of diagnosis in the evaluation of vacuum-assisted stereotactic or core needle breast biopsies is presented. A total of 32 pathologists participated in a blinded evaluation of the biopsies. Each case was evaluated independently by two participating pathologists. A total of 1,357 cases were reviewed. The histopathological reports of the biopsies made by the two consulting pathologists were compared. The concordance rate of the first and second consulting pathologist was 93% for the B-classification. In general, the level of diagnostic agreement was very high for well defined, benign and malignant lesions. Some of the discrepancies resulted from the incorrect application of the B-classification. Discrepancies in the reports were also due to divergent interpretation of benign and "borderline" lesions. The protocol for the blinded evaluation of breast biopsies in two rounds assured a high level of quality. In conclusion, prerequisites for the success of a mammography screening program are interdisciplinary consensus conferences and audit rounds involving pathologists.

[Myxofibrosarcoma]. / Das Myxofibrosarkom.

The myxofibrosarcoma is presented as a special entity of soft tissue tumors and differentiated from the myxoid variant of malignant fibrous histiocytoma to which it was often related in the past. Four own cases are described showing the important aspects of this neoplasm. The myxofibrosarcoma can be characterised as a nodular, myxoid tumor which arises in the subcutaneous tissue of the extremities of elderly people (age-range: 68-72 years) and commonly has a favourable prognosis. The histological appearance is dominated by fibroblast-like cells which are usually embedded in a mucoid matrix or less often form highly cellular, sharply delineated areas. A coarse plexiform capillary pattern and an onion-like arrangement of cells around small arteries contribute to the typical histological picture and are helpful diagnostic features. The difficulties of differential diagnosis between the myxofibrosarcoma and other soft tissue tumors are discussed in detail.

Experimental-induced sarcomas after intra-articular injection of 9-10-dimethyl-1-2-benzanthracene.

The authors describe an experimental study on rabbits whereby the development of sarcomas was induced following injection into the knee joint with 9-10-dimethyl-1-2-benzanthracene. The results of the experiment are in contrast to those of other authors as no "synovialoma" or synovial sarcoma developed but only morphological patterns which might belong to malignant fibrous histiocytoma and occasionally fibrosarcoma. In accord with our results the hypothesis is discussed that all malignant mesenchymal neoplasias result from a not clearly identifiable pluripotent mesenchymal stem cell.

[Cytodiagnosis of malignant non-Hodgkin's lymphomas in effusions (author's transl)]. / Cytodiagnostik maligner Non-Hodgkin-Lymphome in Ergüssen der serösen Körperhöhlen.

Body cavity effusions in malignant non-Hodgkin's lymphomas, particularly in the early stages of those neoplasms, are rare in comparison to the far more common effusions in other malignant diseases and in inflammatory processes. Therefore, the cytological differential diagnosis is of great importance. Of 7,000 pleural and 1,700 ascitic effusions, only 42 cases were malignant non-Hodgkin's lymphoma and in 30 lymphoma was suspected. When lymphoma is suspected, particularly low-grade lymphoma, there are great difficulties in making a differential diagnosis. Using the more or less typical cellular and nuclear criteria of the various lymphoma types, an attempt was made to classify the unequivocal lymphomas according to the Kiel classification of malignant non-Hodgkin's lymphomas. In principle these criteria are the same in cytological and histological examinations. In 31 cases the lymphoma subtype could be specified and confirmed in part by subsequent histological examination. Apart from the suspect lymphoma cases (40%), cases of a low grade of malignancy were predominantly observed (28%). Lymphomas with a high grade of malignancy were less frequently encountered (15%), a proportion similar to that of unclassifiable lymphomas (16%). Apparently the cytological and karyological criteria are not yet adequate to classify lymphomas from conventionally prepared cytological specimens with a higher degree of accuracy.

[The effects of flavonoids on rat liver during chronic palloidin intoxication/Morphological and biochemical studies (author's transl)]. / Zur Wirkung von Flavonoiden an der Rattenleber bei chronischer Phalloidin-Vergiftung. Morphologische und klinisch-chemische Untersuchungen.

Continuous intraperitoneal administration of phalloidin (0.5 mg/kg body weight/day) leads to an alteration of intracellular contractile acto-myosinfilaments in rat liver. The hepatocytes show an accumulation of fibrillar material with some loss of contractile function of the pericanalicular web. Biochemically an increase of serum transaminases and alkaline phosphatase occurs. Histochemically the liver exhibitis changes in the distribution of some hepatocellular enzymes. The influence of the flavonoid (+)-cyanidanol-3 on these phalloidin-induced lesions was studied by histochemical, immunofluorescence and biochemical methods. The results imply, that (+)-cyanidanol-3 is probably protecting the plasma membrane of hepatocytes and therefore reduces the entrance of phalloidin into the cytoplasm. In addition an increased activity of the reticuloendothelial system was observed, perhaps resulting from the flavonoid administration. Both effects could be discussed as mechanisms of flavonoid action in the liver.