Intracranial desmoplastic small-cell tumor. Report of a case.

We report a case of desmoplastic small-cell tumor occurring in the CNS in relation to the tentorium in a 24-year-old man. Morphologically, the neoplasm had the typical appearance of small, round tumor cells of primitive appearance growing as well-defined nests separated by abundant desmoplastic stroma. The diagnosis was confirmed through the demonstration of immunoreactivity for keratin, desmin, and neuron-specific enolase and the detection by Southern blot analysis of a unique gene resulting from the fusion of the WT1 gene in chromosome 11 and the EWS gene in chromosome 22. This is the first documented instance of the occurrence of this tumor type at a distance from a mesothelial-lined surface.

Chronic lymphocytic leukaemias and non-Hodgkin's lymphomas by histological type in farming-animal breeding workers: a population case-control study based on job titles.

OBJECTIVES: A population based case-control study was conducted in a highly agricultural area in the north east of Italy to evaluate the association between farming and animal breeding and the risk of developing non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). METHODS: Occupational histories and other data were collected by personal interview on 164 NHLs, 23 CLLs, diagnosed in 1988-90, and on 977 controls. This paper only reports the results of the analysis relative to the coding of job titles through the modified International Labour Office (ILO) classification. Estimates of odds ratios (ORs) for occupational variables were calculated, after adjustment for sex, age, altitude of municipality, first degree familiarity, and previous Herpes zoster infection. RESULTS: From the analysis of the most frequent occupational categories, no occupation showed a significantly high risk. When the two job titles farmers only and farmer-breeders who are also involved in animal breeding are classified within the extremely varied occupation of agriculture or animal-breeding or fishing, a high risk for NHLs and CLLs is seen in the farmer-breeders (OR 1.79, 95% CI 1.22 - 2.63). Analyses according to histological type show that the risks are concentrated in CLLs and in low grade NHLs. No effect or trend by period at work or duration of employment in farming and animal breeding was found. CONCLUSION: Subjects working in agriculture associated with animal breeding are at high risk of NHL/CLLs, particularly CLLs and low grade NHLs. This finding could be related to the use of chemicals in agriculture or to exposure to animal transmitted diseases or specific chemicals used in animal breeding.

Gastro-intestinal stromal tumors: an ultrastructural reinterpretation of the clear cell component.

The histology, immunohistochemistry and ultrastructure of six gastro-intestinal stromal tumors of the stomach (GSTs) showing a focal to diffuse clear cell component are reported. At light microscopy, all GSTs had typical histopathological features with one case additionally displaying stromal myxoid changes and scattered multinucleated giant cells. Immunohistochemically, 6 of 6 GSTs stained positive for vimentin, 2 of 6 for smooth muscle specific actin and 1 of 6 for desmin. At electron microscopy, GSTs showed microfilaments with focal densities as well as other smooth muscle features, such as subplasmalemmal linear densities and foci of external lamina. Ultrastructural appearances of tumor cells with clear cell features showed these not to be an artifact of fixation, but the expression of an unusual cytophagocytic activity. Inclusions of auto- and heterophagocytic nature were found responsible for the origin of the large, mostly lipidic vacuoles which displaced cell nuclei peripherally in a signet-ring fashion. It is concluded that such previously unrecognized features are ultrastructural aspects of GSTs with smooth muscle differentiation.

Intralesional administration of I-131 labelled monoclonal antibodies in the treatment of malignant gliomas.

The authors report their preliminary experience with the use of radiolabelled monoclonal antibodies (MAb) as an adjuvant treatment for 33 malignant gliomas. MAbs employed in this study are raised against Tenascin (TN) which is an antigen of the extracellular matrix of the tumour. It has also been found in neoplastic cells but never in normal brain tissue. This therapy is aimed to give a local high dose radiation (boost) while sparing healthy brain structures. This treatment has always been well tolerated and no adverse reactions at the level of CNS or major extraneural organs has been observed. Significant improvement of median survival has been obtained but this result should be cautiously evaluate since the study is non-randomized. Comparison with other current adjuvant technique is briefly discussed.

Biologic characterization of pleural metastases from lung adenocarcinoma: description of the new DV90 cell line.

AIMS AND BACKGROUND: The characterization of pleural metastases from lung adenocarcinoma is often limited to single biologic features. METHODS: The present paper describes the cellular kinetic parameters, as well as immunocytochemical, ultrastructural and genetic characteristics of the new DV90 cell line, established from the pleural effusion of a stage IV lung adenocarcinoma. RESULTS: The cell line has a diploid DNA content, a doubling time of 24 h and 7% cloning efficiency, it is tumorigenic in nude mice. Ultrastructural investigation revealed the typical features of lung adenocarcinoma; the diagnosis was confirmed by its immunohistochemical reactivity with a panel of monoclonal antibodies specifically capable of identifying adenocarcinoma cells. Genetic analysis revealed a 46 X, -Y, +8, der (6)t(6?)(q27;?) karyotype and hyperexpression of the protein codified by genes Her2/Neu and p53. CONCLUSION: The importance of multidisciplinary biologic characterization in identifying the origin and biological behavior of pleural metastases deriving from lung adenocarcinoma is discussed.

Intralesional radioimmunotherapy of malignant gliomas. An effective treatment in recurrent tumors.

BACKGROUND: Intralesional radioimmunotherapy (RAIT) may improve the management of malignant gliomas whose prognosis is, at present, very poor. Current treatment modalities (e.g., surgery, radiotherapy, and chemotherapy) may prolong survival by a few months but cannot prevent tumor recurrence. METHODS: Following one or more surgical operations, radiotherapy, and chemotherapy, 24 patients with recurrent malignant gliomas (23 brain and 1 spinal cord) underwent RAIT with 2 murine monoclonal antibodies (MoAb), BC-2 and BC-4, raised against tenascin (TN). This antigen is expressed in large amounts in the stroma of glial tumors but not normal brain tissue. The isotope used was iodine-131 (131I). The radiolabelled antibodies were injected directly into the tumor by means of a removable catheter or an indwelling catheter placed in the site of disease at the time of craniotomy. The patients were admitted to the protocol if histochemical analysis of their tumors demonstrated the presence of TN in high abundance. Biodistribution and dosimetry of an intralesional tracer dose (1 mg MoAb and 37 MBq 131I) were studied. RAIT was performed by the administration of escalating doses of radioiodine, ranging from 15 mCi to 57 mCi. In many cases, RAIT was was repeated two, three, or four times (on 8, 3 and 4 patients, respectively). RESULTS: Pharmacokinetic data resulted, on average, as follows: the 24-hour tumor/background ratio was 16.6; the percentage of injected dose concentrated per gram of tumor at 24 hours was 2.4%; and the effective half-life of the MoAb at the tumor was 74.5 hours. The mean radiation dose to the tumor was 36.48 cGy per MBq of 131I injected. Both systemic and brain toxicities were absent, while human anti-mouse antibody production after MoAb administration occurred in only a few cases. At present, 17 patients are assessable, with a median survival time of 16 months. Objective responses consisted of 5 tumor stabilizations (median time, 9 months), 3 partial remissions (11 months), and 3 complete remissions (15 months).

Glioblastoma therapy by direct intralesional administration of I-131 radioiodine labeled antitenascin antibodies.

Thirty patients with recurrent glioblastomas (29 brain, 1 spinal cord) received intralesional radioimmunotherapy aiming to control the progression of the tumor after surgery and radiotherapy. The BC-2 and/or BC-4 murine MAbs (Sorin-Biomedica, Saluggia, Italy) were utilized. They strongly react against tenascin (TN), which is an extracellular antigen expressed in large amounts by the stroma of glioblastoma but not by normal brain. The MAbs were labeled with I-131 and were injected directly into the tumor mass to maximize the antibody concentration in the tumor and to irradiate the neoplastic cells. The dose consisted, on average, of 3 mg antibody and 1100 MBq I-131. In most cases the radioimmunotherapy (RIT) applications were repeated two, three, or four times. No systemic adverse reactions were recorded. The brain tolerance to direct antibodies injection was quite good. The antibody concentration in the tumor was high and the MAb residence time in neoplastic tumor was prolonged. Consequently the mean radiation dose to the tumor was high: > 25,000 cGy/cycle. Of 23 evaluable patients, we recorded 7 tumor stabilization (lasting, on mean, 9.1 mo), 4 partial remission (10 mo), and 4 complete remission (18 mo). The overall response rate was 34.7%.

Radioimmunotherapy of gastrointestinal cancer and glioblastomas.

Two groups of patients with gastro-intestinal (GI) tumours (41) and recurrent glioblastoma (GBM), (17) underwent radioimmunotherapy after the failure of traditional treatments. A number of different MAbs were employed (anti-CEA and anti-Tenascin) which were labelled with I-131. The radiopharmaceuticals were administered by the intraperitoneal and intratumoral routes. As a rule the cycles were repeated to enhance the effectiveness of RIT. No significant early or late adverse effects were recorded. HAMA development was observed in all GI cases but only in a few GBM patients. The cumulative dose delivered to the target tumors was considerable (mean 8,900 cGy) in the GI group, and was much higher in the GBM patients (mean 51,700 cGy) owing to the particular modality of injection. Survival improved in both series of patients. The objective responses to RIT were promising: in the GI group 10 complete remissions (CR) and 6 partial remissions (PR) were observed, while in the GBM group 3 long-lasting CRs and 3 prolonged PRs were documented.

Hyalinizing trabecular adenoma of the thyroid. Report of two cases, with cytologic, immunohistochemical and ultrastructural studies.

The cytologic, histologic, immunocytochemical and ultrastructural features of 2 cases of hyalinizing trabecular adenoma (HTA) of the thyroid are described. The difficulty of a cytologic diagnosis and the need for an immunohistochemical profile of the lesions for a final histologic diagnosis are emphasized.

Treatment of intracranial human glioblastoma by direct intratumoral administration of 131I-labelled anti-tenascin monoclonal antibody BC-2.

Ten patients with bulky brain glioblastoma, recurring after surgery, radiotherapy or chemotherapy, underwent direct intralesional radioimmunotherapy (RIT) using a monoclonal antibody (MAb), BC-2, raised against tenascin and labelled with 131I. Tenascin, the BC-2-recognized glycoprotein, is an antigen expressed by the stroma of malignant gliomas but not by normal cerebral tissue. Preliminary studies in animals have demonstrated the ability of anti-tenascin radiolabelled MAbs to detect and reduce tumours. A mean MAb dose of 1.93 mg (corresponding to 551.3 MBq of 131I) was injected directly into the tumour by means of a stereotaxic technique. Both systemic and local toxicity were negligible. After 24 hr, average tumour BC-2 uptake was 4.9% per gram and its effective half-life in neoplastic tissue was 66.5 hr: a mean radiation dose to target tissue of 36.48 cGy per MBq of injected 131I was delivered. Normal brain tissue and the major organs were spared. Most patients underwent multiple injections, reaching a cumulative tumour radiation ranging from 7,000 to 41,000 cGy. RIT failed to achieve any result in 4 of the 10 patients; in 3, the disease was stabilized; in the remaining 3, CT scan or NMR revealed 2 partial remission (greater than 50% reduction in tumour volume; PR) and I complete remission (CR). One patient with PR relapsed after II months; the other 2 patients were still maintaining their responses at the time of writing, 17 (CR) and 12 (PR) months after injection.

Treatment of metastatic colorectal cancer by means of specific monoclonal antibodies conjugated with iodine-131: a phase II study.

Eighteen consecutive patients with advanced and/or metastatic colorectal carcinoma have been treated with intraperitoneal administration of radiolabelled (iodine-131) monoclonal antibodies raised against different antigens associated to these kinds of tumours: anti-CEA FO23C5, anti-CEA BW494/32, anti-TAG B72.3, AUA1. The doses of isotope ranged between 21 and 150 mCi (777-5550 MBq) which delivered a radiation dose to the target tumour from 768 to 4628 cGy. Thirteen patients were previously treated with conventional regimens which consisted of chemotherapy (5-fluoracil with or without other anti-neoplastic drugs) both in adjuvant or palliative setting. Three patients are considered non-evaluable owing to concomitant chemotherapy in 2 and lack of objective parameters in 1. Out of 15 evaluable patients 2 achieved complete remission and 2 partial remission with a response rate of 26.6%. Three stable and 8 with progressive disease have also been registered. The toxicity was negligible consisting of hematologic WHO grade 1 in 7 patients, grade 2 in 1 patient and grade 3 in 1 patient, as well as hepatic WHO grade 1 in 8 and grade 2 in 2 patients. The authors conclude that this innovative way of treatment for advanced colorectal carcinoma seems to offer promising therapy; from these data, therefore, a new trial is justified employing radiolabelled MoAbs in well selected patients with metastatic or locally advanced colorectal carcinoma.

Radioimmunotherapy trials in germ testicular carcinoma: a phase I study.

Two patients with germ cell testicular cancer were submitted to radioimmunotherapy (RIT) by using the monoclonal antibody 131I-radiolabelled (MoAb) H17E2, raised against placental alkaline phosphatase (PLAP). Both patients had been previously treated with repeated chemotherapy regimens assisted by autologous bone marrow transplant (ABMT), that, in the end were unsuccessful, thus necessitating further experimental treatment. RIT was well tolerated and the targeting of multiple neoplastic lesions was satisfactory. Nevertheless, the clinical results of treatment were minimal owing to the extension of the tumour. The data obtained suggest the possibility of applying this form of treatment in patients with minimal residual disease after previous traditional chemotherapy regimens.

Fine needle aspiration cytology in a case of diffuse sclerosing carcinoma of the thyroid.

The fine needle aspiration (FNA) cytologic findings in a rare case of bilateral diffuse sclerosing carcinoma of the thyroid are described. Along with a generally papillary architecture, the FNA biopsy smears showed a number of features not usually seen in thyroid carcinomas: psammoma bodies, an abundance of squamous metaplasia and a dense inflammatory component. The FNA diagnosis was multifocal papillary carcinoma with squamous metaplasia; histopathologic examination made the final diagnosis.

Alveolar soft part sarcoma of the cervix uteri. A case report.

A case of alveolar soft part sarcoma (ASPS) of the cervix uteri of a 32-year old woman is described. Its differential diagnosis from histologically similar tumours is discussed. ASPS has been reported in the cervix uteri in one instance only in the literature. In spite of their unusual localization, these cases have to be recognized in order to avoid improper treatment.

Human papillomavirus (HPV) cervical lesions: results from 300 Italian women studied with DNA hybridization techniques and morphology.

Human papillomavirus cervical infection was investigated in a series of 300 unselected women by comparing morphological diagnoses (cytology and histology) with results of DNA hybridization techniques (filter in situ hybridization of DNA from exfoliated cervical cells and Southern blot analysis of HPV-DNA in cervical biopsy specimens). The prevalence of HPV cervical infection diagnosed by PAP smears was 11.6%. Despite disadvantages, filter in situ hybridization was confirmed to be particularly useful for screening purposes to detect HPV in cervical scrapings. In 3 cases it was the only applicable method for diagnosing "high-risk" HPV infection. Southern blot hybridization of tissue DNA with HPV 16-DNA revealed the presence of this virus in 8 cases, and HPV 31-DNA and HPV 42-DNA in 1 case each.

Improved immunoscintigraphy by subcutaneous injection of 99mTc or 111In labelled F(ab')2 fragments of an anti-melanoma monoclonal antibody.

Technetium-99m and/or 111In labelled F(ab')2 fragments of a melanoma associated MoAb 225.28S were injected i.v. in 80 patients affected by stage I to IV malignant melanoma. Seventy five percent of metastatic lesions already documented by other methods were detected by immunoscintigraphy, which was also capable of detecting a certain number of unknown metastases. However, we observed a lower percentage of positive scans in liver, lung and skin because of the poor tumour to background ratio. In some patients, subcutaneous (s.c.) injection allowed us to visualize documented metastases undetected by i.v. administration. An equal amount of non-specific F(ab')2 fragments (MoAb 4C4) injected s.c. as a negative control showed no positive scans. Clinical studies and chromatographic patterns of patient serum samples suggest that the s.c. route of administration offers, with respect to the i.v. route, the advantage of reducing vascular background and aspecific accumulation in liver, probably because of retention of possible contaminants by the lymphatic system.

Neurofibroma with rhabdomyomatous differentiation: benign 'Triton' tumour of the vagina.

The benign 'Triton' tumour is a neural tumour with benign rhabdomyomatous differentiation: it must be distinguished from the better known malignant counterpart. We describe the first case outside the peripheral soft tissues and the first to be studied ultrastructurally. It also represents the second lesion identified in an adult patient.

Spontaneous "primary biliary cirrhosis" in rabbits.

A syndrome resembling human Primary Biliary Cirrhosis (PBC) and occurring spontaneously in a strain of domesticated rabbits from the Faenza region in Italy, is reported. The syndrome is characterized by histological liver changes consisting of chronic non-suppurative destructive cholangitis and copper accumulation, biochemical and immunological abnormalities mainly represented by an elevation of serum alkaline phosphatase and a positive antimitochondrial antibody test. The abnormalities were not observed in newborn rabbits from the same area nor in control rabbits from the island of Sardinia. A toxic effect related to some environmental factor may be responsible for the disease. Alternatively, a continuous process of partial inbreeding among consanguineous animals may have resulted in a selection of a strain genetically predisposed to the development of PBC. Whatever the etiology, the domesticated Faenza rabbit proves to be an interesting animal model for a chronic nonsuppurative destructive cholangitis, very similar to the human disease known as PBC.