Luisa Arganini

Primary cutaneous B-cell lymphoma: A unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases

The clinical presentation and course, and the morphoimmunologic features of primary cutaneous B‐cell lymphoma (CBCL) were investigated in a series of 83 patients. Fifty‐one patients were male and 32 were female (male‐to‐female ratio of 1.6:1); CBCL primarily involved the elderly (median age, 58 years). A locoregional extension of the disease was quite frequent (86.7%). The neoplastic cells showed a range of appearances reminiscent of the whole spectrum of follicular/parafollicular cells. The antigenic phenotype of tumor cells (CD19+, CD20+, CD22+, CD28+, CD10−, CD5−, MB2+, CD74+/−, CDw75+/−. MT2+/−, surface immunoglobulin+ monoclonal/−) plus the presence of admixed CD14‐ dendritic reticulum cells suggest a mantle‐zone nature for CBCL. The nonaggressive clinical behavior with a substantial tendency to remain localized to a limited area of the skin, the quite good response to nonaggressive treatment, and the dichotomy existing between the enhancement of morphoimmunologic atypism—which parallels the increasing age and growth rate of lesions—and the constant benign overall prognosis on long‐term follow‐up make CBCL a unique type of lymphoma of low‐grade malignancy. Proper recognition of CBCL is mandatory to avoid possible undertreatment or overtreatment of the patients affected.

Expression of transforming growth factor β isoforms in osteosarcoma variants: association of tgfβ1 with high-grade osteosarcomas

Studies on osteosarcoma cell lines point to the potential importance of transforming growth factor β (TGFβ) as an autocrine factor which controls the growth of human osteosarcomas. To define further the role of TGFβ isoforms in these neoplasms, a series of 27 osteosarcomas was studied using immunohistochemical, mRNA in situ hybridization, and reverse transcriptase‐polymerase chain reaction (RT‐PCR) techniques. All 14 central high‐grade osteosarcomas, two telangiectatic osteosarcomas, and one high‐grade surface osteosarcoma showed cytoplasmic immunoreactivity for TGFβ1, ‐2, and ‐3. The expression of TGFβ1 was moderate or diffuse in 14 cases (82·3 per cent), while low expression was detected in only three cases (17·7 per cent). For TGFβ2 and ‐3, only moderate or diffuse staining was observed. Low‐grade parosteal and periosteal osteosarcomas showed low or undetectable levels of TGFβ1, while TGFβ2 and ‐3 were moderately or diffusely expressed. Finally, three dedifferentiated parosteal osteosarcomas were diffusely positive for TGFβ1, ‐2, and ‐3 in the high‐grade component, while in the low‐grade component, available for analysis in two of these cases, TGFβ1 was demonstrated in a few neoplastic cells, and TGFβ2 and ‐3 maintained a diffuse distribution. Statistical analysis of these data showed that high‐grade osteosarcomas had a significantly higher expression of TGFβ1 than low‐grade osteosarcomas, while levels of TGFβ2 and ‐3 were comparable in the two groups (p<0·001; p=0·3; p=0·3, respectively; Fishers exact test). Similarly, mRNA levels of TGFβ1 detected by in situ hybridization were significantly higher (p=0·04, Fishers exact test) in high‐grade osteosarcoma variants, while no differences were found for TGFβ2 and ‐3 mRNA (p=1·0; p=0·2, respectively; Fishers exact test). In addition, mRNA analysis performed by RT‐PCR in seven cases (five high‐grade and two low‐grade osteosarcomas) confirmed the presence of high levels of TGFβ1 in high‐grade osteosarcomas, while low‐grade tumours had low or absent mRNA expression. In conclusion, this positive association suggests that TGFβ1 may be involved in determining the aggressive clinical behaviour of high‐grade osteosarcomas.

Effect of Ionizing Radiation on the Enzymes of the Intestinal Mucosa of Rats at Different Time Intervals after Abdominal Irradiation

The enzyme content of the brush border of the small intestine was measured after exposure of the abdomen of rats to 500 and 800 R, respectively, of gamma radiation from a cobalt-60 source. Enzyme activities determined between 4 hours and 16 days after exposure indicated that there were modifications in lactase, maltase, invertase, alkaline phosphatase, LAP (leucineaminopeptidase), and total protein content in homogenates of different segments of the small intestine. The first demonstrable effect, occurring between 4 and 36 hours after exposure was an increase in enzyme activity, which was more marked after 500 R than after 800 R. Thereafter the depression in enzyme levels was correlated with the degree of abnormality of the epithelium. Recovery was almost complete at 5 days after 500 R. Although the activity of some of the enzymes had partly recovered at that time after 800 R, full recovery to preexposure values had still not occurred at 11 days after exposure. Histologic damage to the epithelium, particu...

Biochemical and morphological changes in the epithelial cells of the small intestine after irradiation

Rats have been sacrificed after abdominal irradiation with sublethal doses at very close intervals. Observation at light and electron microscope have been carried out on the small intestine of these animals in order to try to explain the simultaneous modifications of leucineaminopeptidase (LAP) activity. In connection with the increase of LAP activity no modifications have been evidenced, at the light microscope, in the differentiated cells of the villus where the membrane digestion process takes place. In the crypt-villus junction we observe at the electron microscope a remarkable increase in the number of ribosomes since the early intervals. Also during the return phase to normal activities the cells of the crypt and of the crypt-villus junction show a temporaneous increase in the amount of ribosomes. Shortly afterwards we observe an increase of LAP activity.

Cyclooxygenase-2 in oligodendroglioma: Possible prognostic significance

Cyclooxygenase‐2 (COX‐2) is the inducible form of the enzyme involved in the first two steps of the prostaglandins and thromboxane synthesis. Up‐regulation of COX‐2 is demonstrated in tumors where it can modulate tumoral progression, metastasis, multidrug resistance and angiogenesis. Selective COX‐2 inhibitors are seen with growing interest in the tumors treatment. This present study reviews the COX‐2 expression in 32 primary oligodendrogliomas (24 WHO II; eight WHO III) and two glioblastomas with prominent oligodendroglial features (WHO IV). Immunohistochemical results were compared with survival in order to verify the COX‐2 prognostic significance. COX‐2 positivity was found in 44% tumors. Median survival of the patients with a COX‐2 positive lesion was 37 months; median survival of the patients with a COX‐2 negative lesion was 93 months (P = 0.010). Twenty‐nine percent WHO grade II tumors, 87% WHO grade III, 50% WHO grade IV resulted COX‐2 positive (P = 0.016). In patients affected by WHO grade II oligodendroglioma, median survival was 24 and 96 months, respectively, in COX‐2 positive and negative lesions (P = 0.012). In conclusion, even if further studies on different, homogeneous and larger series in vivo are certainly necessary, it is believed that COX‐2 could really have a prognostic value and can be considered as a possible therapeutic opportunity.

Post-irradiation enzyme activities of rat small intestine: effects of dose fractionation

Fractionated irradiation of the rats abdomen with 1200 R, given in two equal exposures, produces changes in the enzyme activities of the epithelial brush border (lactase, invertase, maltase and leucineaminopeptidase (LAP)) of the small intestinal villi. In animals sacrificed at different times after the second irradiation three phases of enzyme activities could be discerned: (1) an initial phase where the activities increase above those in controls; (2) an intermediate phase where the activities are reduced; and (3) the final phase of return to normal of enzyme activity. The fall and subsequent recovery occurs earlier for maltase and invertase than for lactase and LAP. When the time interval between doses is short (6 to 24 hours), alterations of enzyme activities are analogous to, or more extensive than, those found after a single irradiation. When the interval is longer (48 or 72 hours), the initial phase of increased activity is absent. If the time interval is greatly increased (five days) the effect o...

Merlin Expression in Secretory Meningiomas: Evidence of an Nf2-independent Pathogenesis?: Immunohistochemical study

One of the most common chromosomal regions implicated in the meningiomas tumorigenesis is 22q12 where the neurofibromatosis 2 (NF2) gene resides. The NF2 tumor-suppressor gene encodes for the merlin/schwannomin protein, which is responsible for the inherited disease neurofibromatosis 2. NF2 gene mutations predominantly occur in transitional and fibroblastic meningiomas, whereas the meningothelial variant is less affected. Secretory meningioma is an infrequent meningioma subtype. Its most typical morphologic feature is the presence of intracytoplasmic or extracytoplasmic round hyaline, eosinophilic, and periodic acid Shiff-positive bodies in a lesion frequently otherwise classifiable as meningothelial meningioma. This study reviews the immunohistochemical merlin expression in 14 consecutive secretory meningiomas. Our purpose was to investigate if secretory meningiomas, analogous to meningothelial meningiomas, follow a molecular route of pathogenesis independent of the neurorofibromatosis 2 gene-associated pathway. All meningiomas showed positive immunocoloration involving the majority of the hyaline inclusions and secretory cells; in 12 (86%) meningiomas, a positive immunoreaction was also documented in nonsecretory tumoral cells. Our results may indicate a molecular, besides morphologic, similarity between secretory and meningothelial meningiomas: the almost constant merlin immunohistochemical expression in our series gives evidence for a possible NF2 gene-independent pathogenesis in secretory meningiomas.

Cyclooxygenase-2 (COX-2) overexpression in meningiomas: real time PCR and immunohistochemistry.

Cyclooxygenase-2 (COX-2) is the inducible form of the enzyme involved in the first steps of the prostaglandins and thromboxane synthesis. COX-2 up-regulation is demonstrated in tumors where it can modulate tumoral progression, metastasis, multidrug resistance, and angiogenesis. Experimental data suggest a possible therapeutic use of the COX-inhibitors nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs can block tumor growth through many mechanisms, especially through antiangiogenic and proapoptotic effects. Moreover, NSAIDs can also improve the efficacy of radiotherapy, chemotherapy, and hormonal therapy. This study reviews the COX-2 expression as evaluated through immunohistochemistry and real time polymerase chain reaction (RT-PCR) in 23 meningiomas [14 World Health Organization (WHO) grade I; 5 WHO grade II; 3 WHO grade III; 1 oncocytic meningioma]. At immunohistochemistry all the lesions but 4 (83%) were COX-2 positive. At RT-PCR 9 meningiomas, 8 WHO grade I and 1 WHO grade II, showed a COX-2 expression greater than the reference value (average expression of all meningiomas that we studied). The association between tumor grade and immunohistochemical or RT-PCR COX-2 expression was not significant (P=0.427 and P=0.251, respectively). In conclusion, even if further studies on larger series are necessary, the common COX-2 overexpression in meningiomas may suggest considering the COX-2 inhibitors, alone or in combination with radiotherapy, a potential area of therapeutic intervention in some selected meningiomas.

TGF-beta isoform and receptor expression in giant cell tumor and giant cell lesions of bone.

The authors examined the distribution of tumor growth factor-&bgr; (TGF-&bgr;) isoforms and receptors in 35 giant cell tumor (GCT) of bone in comparison with a group of benign giant cell-containing lesions of bone, including 5 aneurysmal bone cysts, 2 cases of brown tumor of hyperparathyroidism, 3 nonossifying fibromas, and 7 cases of giant cell reparative granuloma. The results of immunohistochemical analysis of GCT showed a complete absence of TGF-&bgr;1 expression in both mononuclear tumor cells and giant cells. Only reactive bone present within the tumor showed an intense immunoreactivity. Transforming growth factor-&bgr;2 and TGF-&bgr;3 were detected in the majority of cases (97.1% and 82.8%, respectively), whereas TGF-&bgr; receptor type I (TGF-&bgr; RI) and type II (TGF-&bgr; RII) were diffusely expressed in all cases. Reverse transcription-polymerase chain reaction (RT-PCR) analysis performed on 10 GCTs with specific oligonucleotide primers demonstrated the presence of mRNA transcripts for TGF-&bgr;1, 2, 3, and for TGF-&bgr; RI and RII. Quantitative measurements of TGF-&bgr;1 in conditioned media from primary cultures of GCT showed undetectable or very low amounts of the cytokine (0–23 pg/mL). The results of immunohistochemical analysis showed that all giant cell-containing lesions of bone were at least focally positive for the 3 isoform of TGF-&bgr;, with positivity present both in osteoclast-like giant cells and mononuclear cells, and diffusely positive for TGF-&bgr; RI and RII. Reverse transcription-polymerase chain reaction analysis conducted on samples from 3 nonossifying fibromas and 1 giant cell reparative granuloma confirmed the expression of the corresponding mRNA. In conclusion, according to the current data, GCT of bone can be distinguished from other giant cell-containing lesions of bone on the basis of the absence of TGF- β1 expression at the protein level, which appears to be the result of posttranslational regulation processes.

Oligodendrogliomas Lacking O6-Methylguanine-DNA-Methyltransferase Expression

Abstract O6-Methylguanine-DNA-Methyltransferase (MGMT) is a DNA repair protein considered to be a chemosensitivity predictor. We evaluated the immunohistochemical MGMT expression in 28 consecutive oligodendroglial tumors (21 oligodendrogliomas, 5 mixed oligoastrocytomas, and 2 glioblastomas with prominent oligodendroglial features; 13 treated with CCNU) and compared it with that of 13 glioblastomas. Twenty-six (93%) oligodendroglial tumors were MGMT-negative, 2 (7%) were MGMT-positive. Twelve (92%) patients treated with CCNU had MGMTnegative lesions and their median survival was 73 months; 1 patient had an MGMTpositive oligodendroglioma and is alive at 28 months. Three (23%) glioblastomas were MGMT-negative and 10 (77%) MGMT-positive. The lower MGMT expression in oligodendroglial tumors compared to glioblastomas (P <0.05), which have different chemosensitivity, suggests a possible role of MGMT in the determination of chemoresistance. Nevertheless, the heterogeneous outcome of our MGMT-negative oligodendroglial tumors treated with CCNU, indicates that MGMT expression alone is insufficient to predict the response to alkylating drugs, presumably because of the numerous mechanisms involved.