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.

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.

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.

[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.

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.

The adenoma-carcinoma sequence applies to epithelial tumours of the papilla of Vater.

Adenomas of the papilla of Vater are relatively rare tumours. They are of particular interest, not only because of their particular topography, but also because the adenoma-carcinoma sequence - accepted in the colorectum - has also been postulated to apply to the papilla of Vater. In fact, ampullary adenoma is often considered to be a precancerous lesion. To investigate this hypothesis, we reviewed the surgical specimens obtained during Whipple's procedures carried out to treat histologically confirmed carcinoma of the ampulla. A total of 37 surgical specimens obtained since January 1991 were reexamined for the presence of coexisting adenomatous structures. Such adenomatous residues were confirmed in 24/37 (65 %) cases. In 13/37 (35 %) cases, no residual adenoma was found. A comparison of the two groups revealed that detection of coexisting adenomatous structures decreased with increasing tumour progression. In similar manner, this also applied to the degree of malignancy: with increasing grade of malignancy the rate of detectable adenomatous structures decreased significantly. It may be assumed that these observations are due to the 'overgrowth' of preexisting adenomas by carcinomatous tissue. Further evidence is provided by the histological observation of transitional stages from adenoma with mild, moderate and severe cellular atypia to invasive carcinoma. These findings support the hypothesis of an adenoma-carcinoma sequence.

[Epithelioid hemangioendothelioma of the heart in association with myelodysplastic syndrome]. / Epitheloides Hämangioendotheliom des Herzens in Assoziation mit einem myelodysplastischen Syndrom.

The case of a primary cardiac epithelioid hemangioendothelioma (EHE) arising multifocally in the papillary muscle of the tricuspid valve and the deeper trabecular muscle in a 68-year-old male with myelodysplastic syndrome is presented. The tumor was an incidental autopsy finding. Histologically the tumor is characterized by proliferation of plump epithelial-like endothelial cells with the vascular differentiation being mostly expressed at a cellular level in the form of cytoplasmic vacuoles. In the differential diagnosis, metastatic carcinoma, cardiac myxoma as well as other epithelioid vascular neoplasms should be considered. EHEs are indolent tumors of intermediate malignancy with the potential to metastasize, even after a long time. Primary cardiac EHE is extremely rare. To our knowledge, only four EHEs of the heart have been reported in the literature. We believe, this is the first report of a cardiac EHE in this localization and the first one in association with myelodysplastic syndrome.

[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.

Pathomorphological and histological prognostic factors in curatively resected ductal adenocarcinoma of the pancreas.

The fate of patients with potentially resectable carcinomas is not only determined by the pTNM tumor stage, but also possibly by tumor-biological factors. The aim of this study was to identify these prognostic factors in patients undergoing primary curative (R0) resection. The study retrospectively analyzed 113 patients with ductal adenocarcinoma who were operated on between 1986 and 1995. R0 resection was able to be performed in 93 patients. Lymph node metastases were found in 73%. The rates of lymph vessel and perineural invasion were 83.5% and 45%, respectively. Among the 25 carcinomas without lymph node metastases, 64% already had lymph vessel invasion and 48% had perineural invasion. The cumulative 5-year survival rate of the 91 surviving patients analyzed was 10.5%. Depending on the tumor stage we found a significant difference in 5-year survival rates between patients without lymph node metastases (26.5%) and those with lymph node involvement (5%) (P = 0.008). A multivariate analysis only identified lymph vessel invasion (L0/1), tumor size (< or = or < or =2 cm), and tumor grading (G) to have significant and independent prognostic value. Lymph vessel invasion, tumor size, and tumor grading proved to be independent factors determining long-term prognosis.

[Multilocular thyroid gland ectopy]. / Multilokuläre Schilddrüsenektopie.

HISTORY AND CLINICAL FINDINGS: A 86-year-old woman was hospitalized two days before death. Her past history included essential hypertension and joint pain. Electrocardiography and laboratory findings revealed an acute myocardial infarction. Chemical laboratory examination demonstrated hyperthyroidism. The x-ray of the chest showed a tumor-like mass in the right lung and a nodular goiter with focal changes. Sonographically a tumor in the left colon was diagnosed. Inspite of intensive care the patient died two days later of cardiogenic shock. AUTOPTIC DIAGNOSIS: The autopsy revealed a transmural myocardial infarction with rupture of the heart wall. An adenocarcinoma of the rectum infiltrating the perirectal fatty tissue was diagnosed. Metastases were absent. Additional to an eutopic nodular goiter there was ectopic thyroid tissue in the lung, as a tumour mass under the visceral pleura, in the pelvic cavity and in the skeleton. The histologic findings revealed a close resemblance to the thyroid gland in normal anatomical position. In small foci in the eutopic and ectopic thyroid tissues there were signs of hyperthyroidism. There was no evidence of malignancy. CONCLUSION: One should always keep in mind that manifest hyperthyroidism, not explicable on the grounds of the thyroid findings in normal anatomical position can point to ectopic (multilocular) thyroid tissue, especially when there are "tumours" of uncertain origin.

Prognostic factors in the operative treatment of ductal pancreatic carcinoma.

BACKGROUND AND AIMS: The average 5-year survival rate following resection of a ductal adenocarcinoma of the pancreas is 10%, worldwide. Despite increasing resection rates, only about 20% can be operated on with curative intent. A differential histopathological analysis of the resected tumors may help to justify expanding the surgical procedure by extended lymph-node dissection. PATIENTS/METHODS: Between January 1986 and December 1995, a total of 113 patients underwent resection with curative intent for a ductal pancreatic carcinoma with regional lymph-node dissection. All histological findings were reviewed and reclassified in accordance with the 1997 Union Internationale Contra la Cancrum (UICC) classification. Survival data for all of these patients were obtained from family doctors and registration offices. Independent prognostic factors were statistically analyzed. RESULTS: Of the 113 patients, 93 received an R0 resection. The postoperative mortality rate was 2.2% (2 of 93). More than one-half of the tumors had a diameter of between 2.1 cm and 4 cm. Among the 22 tumors measuring up to 2 cm in diameter, 41% already had lymph-node metastasis and 86% invasion of the lymphatic vessels. Carcinomas measuring between 4.1 cm and 6 cm were all associated with lymph-vessel invasion. Perineural invasion was present in 50% of the tumors. A noteworthy finding was the fact that 64% of the 25 tumors with negative lymph nodes had lymph-vessel invasion, and 48% perineural invasion. The cumulative 5-year survival rate of the R0-resected patients was 10. 5%. Patients with lymph-node-negative stages survived significantly longer (26.5%) than patients with lymph-node-positive stages (5%). Furthermore, a significant difference was seen between pN1a and pN1b (16.7% vs 2.2%). Multivariate analysis identified tumor grading, tumor size and lymph vessel invasion as independent prognostic factors. CONCLUSIONS: Apart from the factors tumor size and tumor grading, lymph-vessel invasion appears to be of special significance for the long-term prognosis. Already in the pN0 stage, the latter was present in 64% of the cases and must be considered a precursor of lymphogenic metastasization. Since lymph-vessel invasion was demonstrated in 86% of tumors measuring less than 2 cm, the therapeutic consequence for all ductal pancreatic tumors is an extended lymphatic and soft tissue dissection that goes beyond the regional lymph-node stations.

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.

Highly sensitive DNA typing for detecting tumors transmitted by transplantation.

DNA typing of a variable number of tandem repeats (VNTRs) and of short tandem repeats (STRs) is a modern forensic method for the identification of biological material. In many cases, amplification by the polymerase chain reaction (PCR), especially of STRs, allows DNA typing of minute amounts of or degraded DNA. Here we describe the successful use of forensic DNA typing to clarify the origin of a malignant tumor. We report two cases of metastatic malignant melanoma of unknown origin that developed a few months after transplantation in two recipients of kidneys from the same donor. Fresh metastatic tissue and blood from the first recipient, reference DNA of the donor, and only paraffin-embedded tissue from the second recipient were available for analysis. To investigate whether the melanoma originated in the donor, DNA analysis of nine polymorphic loci was performed. The results of the analysis showed that, in both cases, the tumors were genetically different from the recipient DNA but matched the donor DNA. One incident of allele loss was attributed to a mutation event. We conclude that the metastatic melanoma in both recipients originated in the donor and was transmitted by renal transplantation.

[Churg-Strauss syndrome with right ventricular tumor]. / Churg-Strauss-Syndrom mit rechtsventrikulärem Tumor.

HISTORY AND CLINICAL FINDINGS: A 47-year-old woman was admitted because of diarrhoea (3-5 stools daily) for 9 days, weakness for 3 weeks and painful wrist swelling, arthralgia and hyperesthesia over the medial aspect of the right thigh for 6 weeks. For 6 years she had been treated for asthma. Two operation had been performed for chronic sinusitis. ADMISSION FINDINGS AND INVESTIGATIONS: There was marked eosinophilia (5889/microliter) and thrombocytopenia (96,000/microliter), markedly increased serological inflammatory parameters and a raised total IgE level (134 IU/ml). The chest radiogram showed pulmonary infiltrates and bone marrow biopsy indicated eosinophilia. Echocardiography revealed a mass, 3 x 8 cm, in the ventral wall of the right ventricle with extension into the outflow tract. DIAGNOSIS, TREATMENT AND COURSE: These findings met the criteria of the American College of Rheumatology for Churg-Strauss syndrome (CSS). On methylprednisolone (1 mg/kg daily) the eosinophil and platelet counts became normal within 5 days and erythrocyte sedimentation rate and the level of C-reactive protein fell. Under cardiopulmonary bypass the tumour was removed, the tricuspid valve replaced, and the right ventricle reconstructed. Histology of the mass revealed it to be an organized thrombus. CONCLUSION: The relationship between the thrombus formation and CSS is unclear. Hypercoagulability connected with the inflammatory process may have played a part in the pathogenesis.

Complete spontaneous remission in a patient with metastatic non-small-cell lung cancer. Case report, review of the literature, and discussion of possible biological pathways involved.

Spontaneous remission of cancer (SR) is defined as a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. We report the case of a 61-year-old man who presented with extensive metatastic disease five months after pneumonectomy for poorly differentiated large cell and polymorphic lung cancer. A vast metastatic tumour mass of the abdominal wall was confirmed histolologically and there was clinical and radiographic evidence of liver and lung metastases. Eight months later, the patient was operated on for a hernia, which had developed in the inguinal biopsy scar and the surgeon confirmed complete clinical SR of the abdominal wall metastases. Again five months later there was no longer any radiologic evidence of liver and lung metastases. Complete remission has persisted more than five years. Histology of the primary and of the abdominal metastases were reviewed by several independent pathologists. SR is an extremly rare event in lung cancer. This is the first documented case of clinically evident visceral metastases of a bronchiogenic adenocarcinoma developing after complete resection of the primary and then showing complete SR. The epidemiology of SR is reviewed and possible mechanisms involved in SR are discussed.

[The Cronkhite-Canada Syndrome. A rare differential diagnosis of generalized gastrointestinal polyposis]. / Das Cronkhite-Canada-Syndrom. Eine seltene Differentialdiagnose der generalisierten gastrointestinalen Polyposis.

HISTORY AND FINDINGS: A 56-year-old man was admitted to hospital because of chronic diarrhoea. 15 months earlier he had begun to notice changes in taste sensation, then nail discoloration and dystrophy as well as alopecia areata. On examination he was also found to have lower leg oedema and cutaneous hyperpigmentation. INVESTIGATIONS: Biochemical tests showed hypoproteinaemia with reduced serum total protein (4.2 g/dl) and albumin concentrations (2.0 g/dl), hypokalemia and hypocalcaemia, as well as zinc and vitamin B12 deficiency. Stool alpha 1-antitrypsin was raised to 5.9 mg/g. Erythrocyte sedimentation rate was 17/26 mm and C-reactive protein was raised to 6.9 mg/dl. Gastroscopy, coloscopy and small-intestine double contrast radiology (after Sellink) demonstrated multiple polyps, histologically revealing pseudopolypoid-inflammatory changes with cystic dilatation, consistent with Cronkhite-Canada syndrome (CCS), a condition characterised by the described endoscopic, radiological and histomorphological changes together with the characteristic ectodermal abnormalities. TREATMENT AND COURSE: At first only symptomatic measures were taken: fluid, electrolyte and protein infusions and administration of zinc and vitamin B12. Stool frequency was regulated by diet and medication. The patient was discharged in much improved general condition and closely followed clinically and endoscopically because of the relatively poor prognosis and frequent occurrence of adenomatous polyps which are at a high risk of malignant degeneration. CONCLUSIONS: In the differential diagnosis of generalised intestinal polyposis only careful investigation by endoscopy and radiology of the entire gastrointestinal tract with biopsies can identify CCS. While treatment is largely symptomatic, its poor prognosis calls for new therapeutic measures.

Childhood hepatocellular adenoma in familial adenomatous polyposis: mutations in adenomatous polyposis coli gene and p53.

BACKGROUND & AIMS: Infantile and childhood liver tumors have been found in 0.42% of individuals with a germline mutation in the adenomatous polyposis coli (APC) gene. This study analyzed a hepatocellular adenoma of a 2-year-old child at risk for familial adenomatous polyposis to identify genetic alterations in hepatic tumors initiated by APC germline mutations. METHODS: Mutation screening was performed for the APC gene (protein truncation test and DNA sequence analysis), p53 gene (complementary DNA cloning and sequencing), and members of the Ras gene family (complementary DNA sequence analysis). RESULTS: Both the mother and child had a germinal CGA-->TGA transition at codon 1451 leading to an Arg1451Ter stop mutation in the APC gene. Loss of the wild-type APC allele as a second hit revealed hemizygosity of the inherited mutation in the tumor. Furthermore, a CGC-->CAC transition in the p53 gene of the adenoma resulted in an Arg-->His missense mutation in codon 175. No loss of heterozygosity was detected at the p53 locus. Ras gene mutations were not found. CONCLUSIONS: Biallelic inactivation of APC gene and p53 mutation are early events in hepatocellular tumorigenesis. Additional reports will confirm whether inherited APC gene mutations between codon 1444 and 1578 increase the risk for hepatic tumors.