[Gastrointestinal stromal tumors. A case of small intestine stromal tumor (SIST) with an uncertain biological aspect]. / Gastrointestinal stromal tumors. Un caso di neoplasia stromale dell'intestino tenue (SIST) dal comportamento biologico incerto.

Tumors of the small intestine are relatively rare. The diagnosis is difficult to establish because the symptoms are vague and non-specific. Although the small intestine constitutes 75% of the length and over 90% of the mucosal surface area of the gastrointestinal tract, only 1 to 2% of gastrointestinal malignancies occur in this segment. Metastases are usually present at the time of diagnosis. The outcome of these patients can be improved if the possibility of a malignant small bowel tumor is considered in all cases of unexplained abdominal pain or gastrointestinal bleeding, especially in younger age. Malignant tumors occur with increasing frequency in distal small bowel with a preponderance of malignant lesions in the ileum compared with the jejunum and the duodenum. Adenocarcinoma is the most common tumor of the primary malignant small bowel tumors, followed by carcinoid, lymphoma and leiomyosarcoma. Mesenchymal tumors of the gastrointestinal tract, traditionally regarded as smooth muscle tumors, have demonstrated different cellular differentiations based on immunohistochemical and ultrastructural features. Therefore the terms leiomyoma and leiomyosarcoma have been replaced by a more encompassing term, gastrointestinal stromal tumor (GIST). The majority of GISTs occurs in the stomach; stromal tumors involving the small intestine (SISTs) are far less common but seem to have greater malignant potential. The clinical a case of a small intestinal stromal tumor (SIST), localised in the jejunum and characterised by an uncertain histological aspect, is presented and a review of the literature is made.

Expression of the neuroendocrine phenotype in carcinomas of the breast.

Neuroendocrine (NE) features are detectable in carcinomas of the breast either as scattered cells immunoreactive for NE markers in carcinoma of the usual type (NOS), or as special type of tumors where the vast majority of the cells display NE characteristics. The former type of lesions, whose biological and diagnostic significance is not clear yet, might reproduce the same phenomenon known to occur in carcinomas of the gastrointestinal tract and pancreas. In the present review we focus on the latter type of lesions, a spectrum of breast tumors largely composed of NE cells. These carcinomas, that we consider the "NE differentiated carcinomas of the breast," are here distinguished from "breast carcinomas NOS with NE differentiation." The diagnostic and histogenetic features of the various types of "NE differentiated carcinomas of the breast," their histological and cytological features and the role and value of ancillary diagnostic techniques, are reviewed. Data of the literature are discussed and related to a relatively large personal series. In addition, divergent differentiation in NE carcinomas of the breast, which is a relatively frequent phenomenon of diagnostic interest but of unknown significance (mainly involving mucinous intra- and extracellular production) is discussed.

Diagnostic cytological features of neuroendocrine differentiated carcinoma of the breast.

Neuroendocrine (NE) features characterize a minority of carcinomas of the breast corresponding to definite subtypes, which cover a wide spectrum of differentiation. Breast metastases from NE tumours of gastrointestinal origin are not rare, and to determine whether NE carcinomas in the breast could be differentiated from other tumours on fine needle aspiration (FNA) we analysed the cytological features of 13 primary NE breast carcinomas of different types (7 carcinoid-like, 5 mucinous and 1 solid spindle cell). Smears of carcinoid-like carcinomas showed specific features that made it possible to differentiate them from other primary tumours, but not from breast metastases of NE carcinomas. These features were: cell clusters with rigid borders, single cells with a plasmacytoid appearance and peripheral cytoplasmic granules evident on Giemsa staining and immunoreactive for chromogranin A. In mucinous NE carcinomas such granules were less apparent, and the cytological features could have been mistaken for those of fibroadenomas, as in the case of non-NE mucinous carcinomas. The solid spindle cell type showed noncohesive fusiform cells and moderate nuclear pleomorphism, a pattern similar to that of atypical carcinoids of the lung.

[Serous cystadenocarcinoma of the ovary with simultaneous breast metastases. Description of a case]. / Cistoadenocarcinoma sieroso dell'ovaio con simultanea metastasi mammaria. Descrizione di un caso.

Metastasis to the breast from extramammary malignancies are rare especially from ovarian carcinoma. We report a case of a 72-year-old woman with a mass in the right ovary and a lump in the left breast together with axillary lymph node enlargement. Both the ovarian and mammary neoplasms were found to be papillary carcinoma with similar immunohistochemical pattern (anti-CA-125: positive; anti-GCDFP-15: negative); some of the axillary lymph nodes showed metastasis with papillary features. On the basis of clinical, morphological and immunohistochemical data we proposed the diagnosis of papillary cystoadenocarcinoma of the ovary with simultaneous metastasis to the breast and axillary lymph nodes.

[Malignant pilomatrixoma of the face]. / Pilomatricoma maligno della faccia.

The authors report a case of malignant pilomatricoma of the right preauricular region in a 66 year old woman. This is a rare neoplasm and only 36 cases have been reported in the literature: 10 in the cervical-facial region and 15 of the scalp. There are problems in differential diagnosis with benign pilomatricoma, basal cell carcinoma, squamous cell carcinoma, parotid masses and the initial stages of cutaneous and subcutaneous cysts. Diagnosis of malignant pilomatricoma is essentially histological. It has a low degree of malignancy but tends to recur after surgery and to metastasize even leading to death. Treatment of choice is a broad surgical excision followed by periodic check-ups. Such exeresis was performed in the case presented and the patient is alive and in good health 67 months after surgery.

Immunophenotypic heterogeneity of hyalinizing trabecular tumours of the thyroid.

AIMS: We studied 12 cases of hyalinizing trabecular tumour of the thyroid gland (HTT) with the aim of reviewing the cytological, histological and immunophenotypic features and of investigating the relationships of HTT with other thyroid neoplasms. METHODS AND RESULTS: Eleven patients were female and one male, aged 8-74 years (median 58). Ten cases had a benign behaviour, while two cases were locally aggressive. Of the latter, one developed distant metastases and the other is a recent case. All patients are alive 6-311 months after diagnosis. Cytologically, HTT was characterized by hypercellular smears with aggregates of roundish cells having features of papillary carcinoma (nuclear grooves, vacuoles) and fragments of fibrous tissue. Histologically, prominent nesting, trabecular growth patterns and a hyaline stroma (partly positive for laminin and collagen type IV) were found. One case was associated with a papillary microcarcinoma. Two additional cases had extensive areas of papillary carcinoma. In one of these, hyalinized papillary stalks were observed. All tumours contained thyroglobulin but not calcitonin. High molecular weight cytokeratin (a marker of papillary carcinoma) was focally positive in 4/12 cases only and thyroperoxidase (a marker of follicular adenomas, but not of papillary carcinoma) was found in 3/12 cases. CONCLUSIONS: The immunophenotypic profile and the morphological features suggest that HTTs are an heterogeneous group of tumours, some of them probably representing variants of papillary carcinoma with hyalinized stroma.

Correlation between pS2 protein positivity, steroid receptor status and other prognostic factors in breast cancer.

The cytosolic levels of pS2, an estrogen-regulated protein, were measured in 100 cases of primary breast cancer and related to several conventional histological and biochemical prognostic factors. The data were statistically analyzed on the basis of two different cutoff point for pS2: 4 and 11 ng/mg of cytosolic proteins. pS2 positivity (cutoff 11 ng/mg) was shown to be associated with small tumor size (p = 0.05), a higher differentiation grade (p = 0.007) and a smaller number of mitoses (p = 0.004), but not with menopausal status, lymph node involvement, cathepsin D levels, or proliferative activity determined by the monoclonal antibody Ki67. With the cutoff of 4 ng/mg, the statistical significance was confirmed only for the number of mitoses (p = 0.03), which was also the most closely related covariate in multivariate analysis (p = 0.008). As regards steroid receptor status, a significant difference was observed between pS2+ and pS2- cases (Chi-square = 8.9; p = 0.04, cutoff 4 ng/mg). in conclusion, pS2 positivity, being preferentially expressed in hormone-dependent cells and related to other well-known positive markers, may either indicate a good prognosis or predict responsiveness to endocrine treatment.

[Diagnosis, treatment and prognosis of gastric stump cancer]. / Diagnosi, trattamento e prognosi del cancro del moncone gastrico.

The authors report 10 cases of gastric stump cancer undergoing operation in the Surgical Department of S. Croce Hospital in Moncalieri between 1978 and 1993, 9 men and 1 woman aged approximate by 67 years. The first operation was a Billroth II with reconstruction according to Polya or Kroenlein. The disease-free period was on average thirty years. In 5 cases the operation was palliative (GEA+Braun) for cancer at fourth stage, in 3 cases radical for cancer in early stage, in 2 cases total gastrectomy+Y for one cancer in early stage and one cancer at II stage TNM. The actuarial survival after 5 years is 50% and this result is satisfactory thanks to four cases of early stump cancer. From our experience, though of only 10 patients, we can deduce that total gastrectomy or degastroresection, in early stage have the same index of survival.

Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice.

We prepared a ricin-antibody conjugate, lacking the ability to bind the galactosidic residues of Sepharose 6B, a so-called blocked immunotoxin. The monoclonal antibody AR-3 was cross-linked to ricin through a thioether bond. Further studies showed that the immunoconjugate suppressed the tumour growth of HT-29 cells in intraperitoneally grafted nude mice, without showing any undesirable ricin toxicity. In this work, to demonstrate the therapeutic activity of the AR-3-ricin conjugate injected into mice bearing subcutaneous tumour, we first evalauted its pharmacokinetic behaviour and biodistribution. The behaviour of the immunoconjugate injected intravenously was almost intermediate between that of the antibody and ricin. Moreover, when the immunotoxin was intravenously administered to nude mice bearing subcutaneous tumour, no therapeutic effects appeared, in accordance with the relatively low permeability of the immunotoxin from the blood to the skin. In contrast, peritumoral treatment produced a strong reduction of the neoplastic nodules without substantial regrowth of the malignant cells. This result was also achieved when the immunotoxin treatment was performed on a well-established tumour. This finding was strictly related to the specifcity of the immunoconjugate, since the analogous treatment with an irrelevant immunotoxin showed therapeutic failure.

Cytologic features of poorly differentiated 'insular' carcinoma of the thyroid, as revealed by fine-needle aspiration biopsy.

The authors report on the cytologic features of six cases of poorly differentiated "insular" carcinoma (IC) of the thyroid, a recently described variety of thyroid tumor intermediate between well-differentiated and anaplastic neoplasms. It is characterized by trabecular and/or alveolar growth patterns, merging with follicular areas, and by the absence of pleomorphism in the tumor cells. Fine-needle aspiration biopsy (FNAB) materials (both smears and cell-block preparations) from six patients were reviewed after the diagnosis of IC was confirmed on the surgical specimen. The following cytologic features were consistently found: high cellularity and necrotic background; low grade of atypia; trabeculae and/or clusters, possibly associated with microfollicles, of cells with poorly defined cytoplasm; and cytoplasmic vacuoles containing thyroglobulin. Nuclear inclusions and grooving of the nuclear surface were additional features. Preoperative diagnosis suggestive of IC might be of value for planning surgical treatment and subsequent therapy.

[Effects of long-term administration of androgens on the breast in transsexual women]. / Effetti della somministrazione a lungo termine di androgeni su mammelle di donne transessuali.

At present the effect on chronic hormonal treatment of normal mammary glands is not known. However, it is thought that high levels of androgens can cause both stromal sclerosis and epithelial atrophy and might provoke fibrocystic mastopathy. The authors describe their own histological studies performed on mammary glands of two women. They underwent mastectomy for transsexualism after prolonged treatment with testosterone.

Ectopic endocrine pancreatic tumour simulating splenic angiosarcoma.

A case of ectopic endocrine pancreatic tumour that had developed within the spleen of a 46-year-old man is reported. The tumour was highly vascularized through the splenic artery, angiographically simulating an angiosarcoma. The histological pattern was typical of an endocrine tumour, and its nature was confirmed by a positivity for keratin, chromogranin A and somatostatin. Foci of atrophic pancreatic tissue were detected in the tumour capsule.

Blocked and not blocked whole-ricin-antibody immunotoxins: intraperitoneal therapy of human tumour xenografted in nude mice.

A blocked immunotoxin, consisting of ricin and AR-3 monoclonal antibody joined by a short thioether bond, was previously synthesized. This conjugate had lost the ability to bind the galactosidic residues of Sepharose 6B, probably because of the steric restraint of the antibody molecule on the ricin B chain. In in vitro assays immunotoxin was active only on cells expressing the corresponding AR-3 epitope. The in vivo activity of our blocked immunotoxin was assessed by injecting it directly into the peritoneal cavity of tumour-bearing nude mice. The animals were i.p. grafted with the HT-29 cell line, which was derived from a human colorectal adenocarcinoma expressing the antigen CAR-3, against which the AR-3 monoclonal antibody is directed. The best protocol tested, to arrive at the optimal regimen for the i.p. blocked immunotoxin therapy, required the administration of the immunotoxin (2 micrograms) on days 4 and 6 after the graft. The mice were killed on different subsequent days to determine the therapeutic effects. Histological sections of the different organs were prepared and stained with haematoxylin/eosin and were also examined by an immunocytochemical method with AR-3 monoclonal antibody to confirm the presence of the relating antigen on the tumour cell surface. The blocked immunotoxin substantially suppressed tumour growth of the grafted HT-29 cells, without showing any undesirable ricin toxicity. Most importantly, established transplanted HT-29 tumour cells treated with blocked immunotoxin almost completely regressed, while under the same conditions the not blocked immunotoxin, an irrelevant immunotoxin, ricin, and the AR-3 alone failed to inhibit tumour growth.

The immunohistochemical detection of lymph node metastases from infiltrating lobular carcinoma of the breast.

Immunological markers improve specificity and accuracy of cell detection, therefore it is important to evaluate their usefulness in improving standard histological procedures. This study investigates whether immunocytochemical techniques increase the accuracy of detection, in axillary lymph nodes, of metastatic cells from infiltrating breast lobular carcinoma (ILC). Fifty cases of ILC reported to be node-negative were selected. New serial sections were cut from a total of 767 lymph nodes, stained with H&E and tested in immunoperoxidase (ABC procedure) with a conventional anti-Epithelial Membrane Antigen (EMA) serum, with a monoclonal raised against human milk fat globule membranes (HMFG-2) and with a monoclonal against 54 kd keratin. Metastases were detected immunocytochemically in 12 cases (24%); in five of these cases metastatic cells were also visible in serial H&E sections. Monoclonals offered no evident advantage over anti-EMA conventional antiserum. Immunocytochemical positivity alone is not sufficient evidence for metastatic invasion since macrophages occasionally appear EMA- and HMFG-2-positive (probably because of secondary incorporation of the antigen), and so an improvement in the accuracy of breast cancer metastatic cell detection in axillary lymph nodes requires a combined histo-immunological approach.

Estrogen- and tamoxifen-induced rearrangement of cytoskeletal and adhesion structures in breast cancer MCF-7 cells.

The cytoskeleton, the shape, and the adhesion complexes of MCF-7 breast carcinoma cells have been studied by fluorescence, phase contrast, and interference reflection microscopy. Cells have been grown in media containing different concentrations of estrogen and with or without the addition of the antiestrogen tamoxifen. The pattern of actin microfilaments and keratin intermediate filaments (tonofilaments) and the distribution of adhesion areas change as a function of the estrogen concentration. When cells are cultured in estrogen-deprived medium, they appear roundish and flattened and adhere firmly to the substratum, with multiple vinculin-positive adhesion plaques at their ventral surface. Upon stimulation with estrogen, these cells display pseudopodial cytoplasmic protrusions and ruffling membranes; in interference reflection microscopy the adhesion areas are mostly localized in these projections. A rearrangement of microfilaments and of tonofilaments in the cell projections and the formation of a dense network of keratin fibers takes place. Tamoxifen affects cellular shape and cytoskeletal arrangement in a way similar to that induced by estrogen. An effect of estrogen-receptor stimulation on the adhesion structures and on the rearrangement of intermediate and actin filaments (and accordingly of the shape and internal structure of breast cancer cells) can be suggested. Such an effect might be direct or mediated through unknown mechanisms; it seems, however, to be independent of the well known estrogenic effect on cell proliferation.

A combined histological, immunocytochemical and biochemical approach in the evaluation of estrogen receptors in breast carcinomas.

Correlation of structural and functional data might lead to better identification of hormone-dependent tumors. Sixty breast cancer specimens, sent to the biochemistry laboratory for estrogen receptor (ER) analysis, were studied here by a combined morpho-functional approach. Histological examination of needle biopsies on frozen tissue blocks showed that 12 cases (10%) were free of tumor cells; these cases mostly proved ER negative. On the other 48 cases, an immunocytochemical reaction was performed on the biopsy sections with a monoclonal antibody directed against p 29, an estrogen receptor related antigen. The staining values for p 29 and the biochemical ER findings were significantly correlated. A combined histological, immunocytochemical study seems to offer advantages in the selection of patients for hormonal therapy.