Biomedical subjects
Publications and source records attributed to G Tallini.
In a totally benign endometrial polyp, double minute chromosomes were shown to contain an amplified and apparently nonrearranged HMGIC gene, expressed in the tumor cells, suggesting amplification of HMGIC through double minute chromosome formation as another hitherto unreported mechanism associated with the development of some mesenchymal tumors.
Oncocytic tumours represent a distinctive set of lesions with distinctive granular cytoplasmic eosinophilia of the neoplastic cells. These cells are called oncocytes because of the "swollen" appearance they have as the result of a striking accumulation of mitochondria. Although generally uncommon, oncocytic tumours are by no means rare and have been reported, with different frequencies, in virtually every organ. A variety of biochemical and molecular changes have been identified, and the aberrant biogenesis of mitochondria in oncocytic cells bears intriguing similarities to that of a group of degenerative disorders known as mitochondrial encephalomyopathies. Although the relationship between the accumulation of mitochondria and the occurrence of tumours is unknown, investigation into the cellular alterations of oncocytes may further our knowledge of a variety of important biological processes such as proliferation, energy production and ageing.
The expression of the beta1C integrin, an alternatively spliced variant of the beta1 subunit, was investigated in human adult and fetal tissues. In the adult, beta1C immunoreactivity was found in nonproliferative, differentiated simple, and/or pseudostratified epithelia in prostate glands and liver bile ducts. In contrast, beta1C was undetectable in stratified squamous epithelium of the epidermis and/or in hepatocytes. Luminal prostate epithelial cells expressed beta1C in vivo and in vitro, but no beta1C was seen in basal cells, which are proliferating cells. Fetal prostate expressed beta1C in differentiated glands that had a defined lumen, but not in budding glands, indicating that beta1C is a marker of prostate epithelium differentiation. The beta1C and the common beta1A variants are differentially distributed: beta1A was found in luminal and basal epithelial as well as in stromal cells in the prostate. In the liver, beta1C and beta1A were coexpressed in biliary epithelium, whereas vascular cells expressed only beta1A. Because we found beta1C in nonproliferative and differentiated epithelium, we investigated whether beta1C could have a causal role in inhibiting epithelial cell proliferation. The results showed that exogenous expression of a beta1C, but not of a beta1A, cytoplasmic domain chimeric construct, completely inhibited thymidine incorporation in response to serum by prostate cancer epithelial cells. Consistent with these in vitro results, beta1C appeared to be downregulated in prostate glands that exhibit regenerative features in benign hyperplastic epithelium. These data show that the presence of beta1C integrins in epithelial cells correlates with a nonproliferative, differentiated phenotype and is growth inhibitory to prostate epithelial cells in vitro. These findings indicate a novel pathophysiological role for this integrin variant in epithelial cell proliferation.
Large cell transformation (LCT) in cutaneous T-cell lymphoma (CTCL) is estimated to occur up to approximately 20% of patients. This morphologic change is associated with aggressive behavior and shortened survival. Our purpose was to identify morphologic and/or immunophenotypic features in CTCL skin biopsies that are predictive of transformation. We analyzed 12 cases of CTCL (three cases of mycosis fungoides and nine cases of Sezary syndrome) that underwent LCT and for which sequential biopsies before and after transformation were available. Eight of 12 cases had pre-LCT marker studies performed on frozen tissue. The histologic and immunophenotypic features of CTCL and LCT were reviewed. Morphologically, CTCL biopsies showed the following: Pautrier microabscesses (five cases), epidermotropism of single lymphoid cells (three cases), and nonspecific histology (four cases). Immunophenotyping prior to transformation showed aberrant loss of T-cell markers (CD5, CD7, CD5 and CD7) in three of eight cases. CD4:CD8 ratios were increased in all cases. Expression of CD25 by the neoplastic lymphoid cells was detected in six of seven cases. LCT immunophenotyping showed additional loss of CD7 in one of five cases and of CD25 in three of five cases. In conclusion, expression of CD25 in CTCL may identify a subset of patients at risk of undergoing LCT.
The diagnosis of marrow involvement in non-Hodgkin's lymphoma (NHL) relies on morphology with support from immunophenotyping by flow cytometry (FCM). We assessed the relative sensitivity of morphology, FCM, and consensus primer polymerase chain reaction (PCR) of antigen receptor genes in the detection of marrow involvement. In 78 of 100 (78%) cases, there was concordance between FCM and PCR. FCM detected more cases of clonality in B-cell neoplasia. There were 40 cases with objective evidence of involvement by B-cell neoplasia. In this group, FCM had a sensitivity of 97.5% (39 of 40); PCR had a sensitivity of 67.5% (27 of 40). In contrast, PCR had a sensitivity of 71.4%, and FCM a sensitivity of 28.6%, in T-cell neoplasia. In all 12 cases with involvement detected by biopsy, there was objective evidence of clonality. However, clonality was detected in four of seven patients with chronic lymphocytic leukemia and in five of eight patients with T-cell neoplasia in the absence of morphologically detectable disease. Clonality was identified in only one of seven patients with B-cell lymphoma in which the biopsy was interpreted as "suspicious but not diagnostic of involvement." We conclude that morphology remains of central importance in the evaluation of marrow involvement in NHL. We show that FCM and PCR identify involvement in the absence of morphologically apparent disease. In B-cell neoplasms, FCM remains the method of choice for the detection of clonality. PCR for T-cell receptor gene rearrangements may be an important adjunct to the diagnosis of marrow involvement in patients with T-cell neoplasms.
PURPOSE: Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. PATIENTS AND METHODS: TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). CONCLUSION: TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.
Malignant tumors of the thyroid gland vary considerably in aggressiveness, ranging from a well-differentiated, clinically indolent, to an undifferentiated, often lethal phenotype. Undifferentiated (anaplastic) thyroid tumors are supposed to be derived, through a process of progression, from previously differentiated neoplasms. A common genetic alteration in thyroid tumors is the rearrangement of the tyrosine kinase-encoding RET proto-oncogene, leading to the generation of chimeric RET/PTC oncogenes. To define the characteristics of the thyroid tumor subset with RET rearrangements, we have investigated its activation by a combined immunohistochemistry and reverse transcription-PCR approach in a series of 316 well-characterized thyroid tumors representative of the main diagnostic groups. RET activation was detected in 81 of 201 (40.3%) papillary carcinomas. It correlated with tumors exhibiting the "classic" morphological features of papillary cancer or with the microcarcinoma subtype (P = 0.017). RET activation in papillary carcinoma was not associated with clinical markers (such as large tumor size, extrathyroidal extension, or metastases) of increased morbidity. Follicular-type neoplasms (61 adenomas and 22 carcinomas), as well as the aggressive poorly differentiated (15 cases) or undifferentiated (anaplastic) carcinomas (17 cases), were negative. This study demonstrates that all thyroid carcinomas harboring activating RET rearrangements exhibit a well-differentiated phenotype, that of papillary carcinoma, and indicates that the subset of RET/PTC-positive papillary carcinomas do not progress to more aggressive, less differentiated tumor phenotypes.
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Poorly differentiated rhabdomyosarcomas are traditionally distinguished from lymphomas by their absence of lymphoid markers such as immunoglobulin or CD20 expression. We have encountered three alveolar rhabdomyosarcomas that were initially diagnosed as lymphoid neoplasms because of the expression of a lymphocytic phenotype in morphologically undifferentiated tumor cells. Subsequent cytogenetic analysis revealed a t(2; 13) in two cases. All cases recurred in the chest wall and showed positivity for muscle markers, such as muscle-specific actin, myoglobin, MyoD1, and/or desmin on subsequent immunohistochemistry. The findings in these three cases lead us to conclude that the presence of a lymphoid phenotype does not absolutely exclude the diagnosis of rhabdomyosarcoma.
Integrin adhesion receptors modulate cell functions, including cell proliferation and survival. The beta 1C integrin, an alternatively spliced form of beta 1A, containing a unique cytoplasmic domain sequence, inhibits cell growth in vitro. In vivo, the expression of beta 1C correlates with a benign, nonproliferative phenotype in epithelial cells. The studies discussed in this article indicate that modulation of cell proliferation, in normal or pathological conditions, might be achieved by the regulated expression of variant integrin subunits.
Subcutaneous angiolipomas are benign soft-tissue lesions consisting of two mesenchymal elements (i.e., adipose tissue and blood vessels) and having distinct clinical features. They usually are multiple, with an obvious male predominance, and hereditary occurrence has been described. Twenty subcutaneous angiolipomas from 10 patients with typical clinical and morphologic features were reviewed. All lesions had a normal karyotype. This finding is in striking contrast with ordinary lipomas, spindle-cell and pleomorphic lipomas, lipoblastomas, and hibernomas, most of which have characteristic clonal chromosomal aberrations. The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggest a different pathogenesis from pure lipomas.
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The high mobility group proteins (HMGs) are a class of low molecular weight, nonhistone, nuclear proteins that bind DNA and function as transcription cofactors. This class includes the HMGI family members HMGI-C and HMGI(Y). Both are not significantly expressed in differentiated adult tissues, including fat, but their expression is induced in proliferating and transformed cells. Their involvement in the development of lipomatous tumors has been recently demonstrated for HMGI-C, which is encoded by a gene located at 12q15, the chromosomal segment often rearranged in ordinary lipomas. The same chromosomal segment is consistently amplified in the ring and giant marker chromosomes of atypical lipomatous tumors (ALTs), a term used to designate tumors previously labeled as well differentiated liposarcomas or atypical lipomas. The involvement of HMGI(Y) is strongly suspected as the gene coding for HMGI(Y) is located at 6p21, a chromosomal segment rearranged in a subset of ordinary lipomas. HMGI-C or HMGI(Y) protein expression was analyzed immunohistochemically in a group of 39 well differentiated adipose neoplasms (19 lipomas and 20 ALTs) of known karyotype using polyclonal antibodies raised against a recombinant protein (HMGI-C) and against a synthetic peptide (HMGI(Y)). The results of this study demonstrate that HMGI proteins are commonly expressed in well differentiated adipose neoplasms. Seventeen of twenty ALTS (85.0%), all of which had ring or giant marker chromosomes with amplification of 12q13-15, strongly expressed HMGI-C. HMGI-C expression was detected in 7 of 11 ordinary lipomas (63.6%) with alterations at 12q14-15 and in one case with an abnormal karyotype that included double minute chromosomes. HMGI-C immunoreactivity correlates with 12q13-15 chromosomal alterations (P = 0.001). HMGI(Y) reactivity was demonstrated in only two ordinary lipomas: one with 6p21 rearrangement and one with normal karyotype. No significant HMGI(Y) expression was found in the ALT group. The finding of aberrant expression of HMGI proteins in well differentiated adipose neoplasms in association with 12q13-15 and 6p21 chromosomal changes supports the proposed pathogenetic role of this group of proteins in the development of adipose tissue tumors.
Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12ql3-15, and atypical lipomatous tumors (ALT) by supernumerary ring chromosomes or giant markers known to contain amplified 12q sequences. In a series of 228 cytogenetically analyzed and histopathologically reexamined ordinary lipomas and ALT, 10 tumors showed unbalanced chromosome-12 aberrations. All 4 tumors with loss of segments from 12q were classified as ordinary lipomas, whereas 5 of the 6 tumors showing gain of 12q material were diagnosed as ALT. One or three extra copies of 12q15-q24 were present in all 5 ALT. We conclude that duplication of 12q sequences may be a sufficient level of amplification for development of the microscopic appearance that characterizes ALT.
BACKGROUND: Malignant mesenchymomas are rare soft tissue tumors that contain two or more distinct histologic subtypes of sarcoma within the same tumor (exclusive of a fibrosarcomatous or hemangiopericytomatous component). They are generally considered high grade neoplasms and are associated with a poor prognosis, although experience with these tumors is limited. METHODS: We report 8 patients seen at our center over the last 22 years and describe the clinical course of a patient with a malignant mesenchymoma arising in the retroperitoneum whose experience typifies the aggressive behavior of this tumor. RESULTS: All eight patients had large, high grade tumors located in the retroperitoneum or thigh. Six of the 8 died of disease and 2 were alive with disease at a median of 30 months from diagnosis. CONCLUSIONS: Malignant mesenchymoma represents a particularly aggressive form of soft tissue sarcoma. Our experience with this disease highlights the need for more effective treatment strategies for these patients.
Human immunodeficiency virus-positive (HIV+) women have an increased risk of lower genital tract dysplasia and neoplasia, and studies of the central lymphoid system suggest that impaired immunosurveillance plays a role in the development of their cervical tumors. Intraepithelial and stromal immunocompetent cell counts were compared in cervical specimens from 50 HIV+ and 50 appropriately matched HIV-women (controls) with low and high grade squamous intraepithelial lesions (SIL), or carcinoma. Each histological class of HIV+ women displayed fewer intraepithelial Langerhans' (S100+) cells (LC) (as already known), and also fewer stromal LC and both intraepithelial and stromal (CD68+) macrophages. LC and macrophages were reduced in all HIV+ patients, whereas reduction of cervical T lymphocytes was found in only immunocompromised subjects (peripheral blood CD4+ T-cell count < 500/microL). A mucosal quantitative deficiency of antigen-presenting cells (APC) thus precedes that of T cells. HIV infection appears to lead to early impairment of mucosal immunoreactivity mainly because of defective antigen presentation. This impairment may be one mechanism underlying the increased frequency of cervical dysplasia/neoplasia, and the enhanced aggressiveness of invasive cancers in HIV+ women.
Cytogenetic analysis carried out in 28 adipose tissue tumors diagnosed microscopically as myxoid liposarcoma (ML) revealed a t(12;16)(q13:p11) chromosomal translocation in 26 of the 28 cases. Morphologically, these tumors were subclassified into the following categories: well-differentiated, six cases: poorly differentiated round cell type, 17 cases: poorly differentiated spindle cell type, five cases. Poorly differentiated ML behaved in a more aggressive fashion than the well-differentiated tumors. The results of this study confirm the consistency and specificity of the t(12;16)(q13:p11) translocation as the genetic marker of ML, support the contention that liposarcomas with round cells belong to the ML category, and confirm Stout's proposal for the existence of a poorly differentiated ML composed of spindle cells. Cytogenetic analysis may be helpful in the differential diagnosis of ML with atypical lipomatous tumors, which is characteristically associated with ring and giant marker chromosomes, and of ML with lipoblastoma, which is typically associated with 8q alterations. The existence of a mixed ML-atypical lipomatous tumor remains questionable. The genetic events associated with the greater aggressiveness of the poorly differentiated types of ML remain to be determined.
Fifty-nine cases of atypical lipomatous tumors (ALT) of soft tissue (atypical lipomas, well-differentiated liposarcomas) were studied morphologically and cytogenetically as part of an international collaborative study. Forty-nine cases were deeply seated (including retroperitoneum), and 10 were superficial. Clonal chromosomal abnormalities were found in 55 cases (93%). Supernumerary ring or giant marker chromosomes (RGCs), the sole consistent alteration, were found in 37 ALTs (63%). They were more common in tumors that were large (p < 0.001), deeply seated (p < 0.005), that contained lipoblasts (p < 0.05), and that had marked cytologic atypia (p < 0.05). In a relatively short follow-up period (average, 3 years), only three of 59 cases recurred, one resulting in the patient's death. All three cases had RGCs. Also, five of the six cases that underwent dedifferentiation had RGCs, indicating that RGCs are associated not only with low-grade malignant behavior (in the form of local recurrence) but also with the potential for tumor progression. When the karyotypic profile of ALT was compared with that of 233 other types of adipose tissue tumors similarly analyzed by the authors, a statistically highly significant correlation (p < 0.0001) was found between ALT and RGCs. These results support the existence of ALT as a distinct tumor subtype that is different from ordinary lipoma and from spindle or pleomorphic lipoma, albeit histogenetically closely related to them. It also supports the proposed pathogenetic link between ALT and dedifferentiated liposarcoma. The association between chromosomal and morphologic findings indicates the potential role of karyotypic analysis in the differential diagnosis of ALT with ordinary lipoma, spindle or pleomorphic lipoma, hibernoma, and myxoid liposarcoma.