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p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor.

The expression of p53 protein, oestrogen receptor protein, epidermal growth factor receptor (EGFR) and overexpression of the c-erbB-2 oncoprotein was examined in a series of 149 primary symptomatic breast carcinomas. Expression of p53 was present in 62 of 146 cases (42.5%) of the invasive carcinoma and one of three cases (33.3%) of ductal carcinoma in situ (DCIS) examined. Statistical associations of tumour oestrogen receptor positivity and lack of p53 protein expression, chi 2 = 19.78 (d.f. = 1), P less than 0.001, positive tumour p53 status and poor tumour grade; chi 2 = 14.1 (d.f. = 2), P less than 0.001, EGFR expression chi 2 = 7.07, (d.f. = 1), P less than 0.01 and tumour c-erbB-2 protein overexpression; chi 2 = 4.61 (d.f. = 1), P = 0.032 were identified. Expression of p53 is rare in invasive lobular carcinoma of classical type (8.3% of cases examined) in contrast to other common types of mammary carcinoma. Non-significant trends of p53 protein expression and increased regional tumour recurrence; chi 2 = 3.20 (d.f. = 1), P = 0.074 and also poorer patient survival; chi 2 = 3.76 (d.f. = 1), P = 0.053 were identified. p53 protein expression is a common event in human breast cancer and is present in both DCIS and invasive mammary carcinoma. Abnormal expression of p53 protein is a feature of both in situ and invasive breast carcinoma, implying that the abnormal p53 protein expression may be implicated in the early stages of mammary carcinoma progression.

Biomarkers, Tumor↗

Overexpression of p53, c-erbB-2 and epidermal growth factor receptor in human breast carcinomas.

Overexpression of p53 protein, epidermal growth factor receptor (EGF-R), and c-erbB-2 protein was assessed by immunohistochemical staining of formalin-fixed, paraffin-embedded tissue from 64 invasive breast tumors. The correlation between abnormal expression of each protein and various disease parameters, including lymph node metastasis and histopathologic type and grade was analyzed. Despite the previous proposal, no significant correlation was found between lymph node metastases and overexpression of each gene in the primary tumors. In addition, some metastatic lesions did not always exhibit overexpression, even if it was evident in the primary tumors. Overexpression of c-erbB-2 protein correlated well with Bloom's histological grading. p53 expression was detected most often in tumors with hyperchromatism and more frequent mitosis. Overexpression of c-erbB-2 protein occurred more frequently in p53-positive tumors. The results indicate that abnormal expression of p53 protein causes genetic instability in the early stage of tumor development, resulting in subsequent overexpression of other oncogenes.

Adenocarcinoma↗

Pulmonary hilar lymph node metastases from lung cancer: evaluation based on morphology at thin-section, incremental, dynamic CT.

PURPOSE: To evaluate the usefulness of a new computed tomographic (CT) criterion for diagnosing hilar lymph node metastases on the basis of the margin between hilar interstitium and lung parenchyma. MATERIALS AND METHODS: The morphology of normal and metastatic hilar nodes was analyzed in seven inflated and fixed human lung specimens. Thin-section, incremental, dynamic CT was then performed preoperatively in 95 patients with lung cancer, and the margins of peribronchovascular hypoattenuated areas were evaluated in 22 of the patients with normal hila. CT-pathologic comparisons were performed at 179 locations where interstitium touched lung parenchyma. The comparison was based on a new CT criterion in which convex interstitial margins indicate nodal metastases. RESULTS: The margins of the interstitia with normal nodes were concave or straight at 94.8% (183 of 193) of the contact sites in the six normal specimens and at 97.3% (436 of 448) of the contact sites on CT scans, whereas the margins of the interstitia with abnormal nodes were convex at 94.7% (54 of 57) of the contact sites in the abnormal specimen. Sensitivity, specificity, and accuracy of three reviewers who used the new criterion were 87.3%, 88.3%, and 88.1%, respectively. CONCLUSION: The new CT criterion is useful for the diagnosis of hilar node metastases in lung cancer.

Humans↗

Back-pack mice as a model of renal mesangial IgA dimers deposition.

Mesangial IgA in IgA nephropathy are dimers with a J chain but no poly-Ig receptor. This molecular structure has led to the hypothesis that these IgA are issued from the lamina propria of mucosal areas, reaching the kidney by way of the peripheral blood. The availability of hybridomas producing IgA dimers provided an opportunity to test this hypothesis in a new experimental model of IgA nephropathy. Mice were injected subcutaneously (back-pack mice) or intraperitoneally with hybridoma cells secreting either monoclonal IgA dimers, or monoclonal IgA monomers. The influence of immune complex formation was also tested in both these models. Renal IgA deposition was investigated 12 days after the injection of hybridoma cells. Backpack mice developed highly vascularized subcutaneous tumors. Mesangial IgA deposits were observed only in dimeric IgA hybridoma back-pack animals. No significant staining was observed in glomeruli from animals injected with hybridoma cells producing monomeric IgA. None of the hybridomas induced mesangial deposition when injected intraperitoneally. This animal model demonstrates the capacity of circulating IgA dimers to spontaneously form mesangial deposits and contributes to confirm the involvement of abnormalities of mucosal immunity in the pathogenesis of IgA nephropathy.

Animals↗

Metastatic melanoma: the spectrum of ultrastructural morphology.

The fine structure of 26 metastatic melanomas, including 13 pigmented and 13 amelanotic tumors, as studied to define ultrastructural criteria for diagnosis. Several important features in addition to melanosome granules were identified. Dendritic cytoplasmic processes were seen in 25 of the 26 cases, cell clusters formed by concentric aggregates of several cells and their processes were present in 18, and microvilli were found on cell surfaces in all cases. The cytoplasm was complex, containing numerous mitochondria, Golgi systems, endoplasmic reticulum, nonspecific filaments, and microtubules. Nuclear morphology was variable. Basement membranes and cell junctions including desmosomes were often encountered, and some melanomas shared features with Schwann cells, including complex membrane interdigitations. All tumors contained melanosomes, although the classic forms were frequently difficult to identify and abnormal variant forms often predominated. Knowledge of the variant melanosome morphology and an understanding of the other fine structural features of malignant melanocytes can help identify those cases that lack classic premelanosome granules.

Adolescent↗

Prepubertal orchidectomy induces thymic abnormalities in aging (NZB X SJL)F1 male mice.

Female but not male (NZB X SJL)F1 (NS) mice develop abnormalities of their intrathymic lymphocyte population in the course of aging. To determine the role played by androgens in this sex-related difference, we monitored the evolution of the cellular composition of the thymus in NS males deprived of androgens by prepubertal orchidectomy. Although in young mice this operation resulted in a twofold enlargement of the thymus, there was no histologic alteration or major change in the surface phenotype and mitogenic reactivities of the thymocytes, which suggests that all thymocyte subsets were increased to the same extent. In 12-mo-old control (BALB/c X SJL)F1 mice, prepubertal orchidectomy also produced an equal expansion (1.4-fold increase) of all thymocyte subsets. In contrast, in 12-mo-old orchidectomized NS males, there was a marked depletion of the thymic cortex and a hyperplasia of the medullary lymphoid tissue reflecting the selective expansion of a subset of phenotypically mature T cells (dull Thy-1+, Lyt-1+2+/-, dull PNA+) together with the emergence of intrathymic surface immunoglobulin-bearing cells. These latter cells probably represented B cells because there was a concomitant augmentation of the mitogenic responsiveness in vitro of thymic cell suspensions to lipopolysaccharide. Such thymic abnormalities induced by prepubertal orchidectomy in old NS males resemble those occurring spontaneously in the NS females. This suggests that the absence of thymic disease in intact NS males is primarily due to a suppressive effect of androgens.

Aging↗

Ultrastructural alterations of the conduction system in mice exhibiting sinus arrest or heart block during Coxsackievirus B3 acute myocarditis.

By light and electron microscopy we studied the sinus nodes and atrioventricular (AV) conducting tissue of six C3H/He mice having coxsackievirus B3 acute myocarditis. Sinus arrest was documented in all six mice, and second- or third-degree AV block was documented in three of the six mice. Although myocarditic changes in the conduction system, especially in the sinus node, were less than those in atrial and ventricular working myocardium, there were distinct abnormalities within both the sinus node and AV conducting tissue in all six hearts. Important ultrastructural alterations were inflammatory cell infiltrates and significant injury of specialized cells and of neural tissue. Specialized cells showed various features of degeneration and necrosis. Neural tissue damage included degeneration of axons and Schwann cells and disorganization of the neuromuscular junctions. Inflammatory cells, particularly macrophages, were often in intimate contact with injured specialized cells and neural tissue. Interstitial edema and bleeding and lymphatic vessel dilatation were also observed. These pathologic changes are considered to play an important role in the development of the documented disturbances of rhythm and conduction.

Animals↗

Sporadic acute non-A non-B hepatitis complicated by aplastic anemia.

A 19-year-old woman developed acute jaundice and abnormal liver tests showing acute viral hepatitis, presumably non-A non-B. The viral hepatitis, on the 4th day after admission, was complicated by aplastic anemia. Therapy with hydrocortisone promptly instituted was ineffective and a bone marrow transplantation was not possible because we could not find a compatible donor. Sixty-five days after admission the patient died of infection by Candida tropicalis. Postmortem examination showed total medullary aplasia with massive impoverishment of all the lymphatic structures and multiple fungal infarctions in the myocardium, lungs, spleen, kidneys, and liver.

Acute Disease↗

Banding studies of chromosomes in a patient with mycosis fungoides.

Chromosomes from a patient with mycosis fungoides were examined in detail with banding techniques. Hyperdiploid cells from a lymph node had common anomalies of certain chromosomes which formed three similar clones. The abnormalities involved chromosomes No. 1, 2, 5, 8, 9, 10, 14, and 18, in addition to an unkwown small metacentric marker (M3). Although there were a number of mitotic cells in peripheral blood cultured both with and without PHA, none of the few cells with abnormal karyotypes was similar to the clonal cells of the lymph node. One of the abnormalities in the lymph node was a 14q rearrangement, which could be the result of a translocation of Nos. 8 and 14 involving a third chromosome, No. 2. An abnormality in the blood resulted from a translocation between the long arms of Nos. 1 and 14. These findings could be useful for studies in which mycosis fungoides is compared with the Sézary syndrome and other lymphoid malignancies.

Bone Marrow Examination↗

[High resolution small parts sonography (7.5 MHz) of the head and neck region].

Frequently, sonography of the head and neck serves only for assessment of the thyroid and arteriosclerotic lesions of the extracranial vessels. This article gives a review of ultrasound of the remaining cervical structures, particularly spaceoccupying lesions. The differentiation between malignant and benign lymphadenopathy or between intraglandular and extraglandular abnormalities of the salivary glands is possible with an accuracy between 90 and 95 %. Limitations of the method lie in the difficult access to the skull basis as well as the retropharyngeal and retrotracheal space.

Diagnosis, Differential↗

Epithelioid sarcoma in children and adolescents: a report of four cases.

Epithelioid sarcoma is an uncommon soft tissue tumor, most prevalent in the extremities of young adults. Youth has been described as a favorable prognostic factor. We describe four patients (two children aged 10 years and two adolescents aged 18 years) with extremity epithelioid sarcoma. Both 10-year-old children had rapid disease evolution and died 3 and 6 months after the diagnosis was made. Both tumors were strict diploid at DNA flow cytometry, but one had an abnormal karyotype (trisomy 2). Both adolescents are disease-free 18 months and 18 years after combined treatment consisting of local resection, regional lymph node dissection, and isolated regional perfusion with cytostatic agents.

Adolescent↗

Extramedullary presentation of chronic myelogenous leukemia with p190 BCR/ABL transcripts.

We present here a rare case of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia having p190 BCR/ABL with a malignant clinical picture of extramedullary blast crisis at onset, followed by rapid evolution to bone-marrow blast crisis. The patient was a 44-year-old woman presenting with leukocytosis and multiple lymph-node swelling in the neck. Lymph-node biopsy revealed a myeloperoxidase-positive blastoma with cell-surface markers of myeloid and T-lymphoid lineages. Fluorescence in situ hybridization and the reverse transcription polymerase chain reaction detected a minor BCR breakpoint but failed to detect a major BCR breakpoint. By single-strand conformation polymorphism and direct sequencing, no alteration in the TP53 gene was found, and no additional chromosomal abnormalities other than Ph were identified. The present case suggests that p190 BCR/ABL is associated with the aggressive course of the disease.

Adult↗

Lymphadenopathy-associated viral antibody in AIDS. Immune correlations and definition of a carrier state.

We investigated whether serologic evidence of lymphadenopathy-associated virus (LAV), an exogenous human T-cell lymphotropic and cytopathic retrovirus, correlated with the acquisition and transmission of the acquired immunodeficiency syndrome (AIDS). Serum from 17 of 25 patients with AIDS contained circulating IgG anti-LAV antibody (all of 5 adults with cancer and 6 of 12 adults and 6 of 8 children with opportunistic infections, with or without Kaposi's sarcoma). All of eight homosexual men with generalized lymphadenopathy or the AIDS-related complex and five homosexual men with AIDS prodromes who subsequently had AIDS were also seropositive. The anti-LAV antibody was not found in 99 of 100 healthy blood donors or in 23 patients with genetic immunodeficiencies, supporting the contention that LAV is unlikely to represent simply another opportunistic microorganism. An AIDS carrier state was indicated by the probable transfer of LAV from asymptomatic, immunologically competent mothers to their offspring. These data offer a basis for the hypotheses that LAV is a marker for AIDS, may be carried and transmitted in the absence of clinical findings or in vitro T-cell abnormalities, and is probably an etiologically important agent in AIDS and its prodromes.

Acquired Immunodeficiency Syndrome↗

Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy.

In a computerized case registry, containing 220 cases of sinus histiocytosis with massive lymphadenopathy (SHML), 23 patients were identified with clinical or routine laboratory findings suggestive or diagnostic of immune dysfunction. We divided the abnormalities into hematologic autoantibodies (nine patients), glomerulonephritis (three patients), Wiskott-Aldrich syndrome (two patients), joint disease (nine patients), unusual infections (three patients), and miscellaneous (six patients). Nine of the patients had more than one finding prompting inclusion in this study. In five patients, at least one abnormality preceded the onset of SHML. A major difference between this subgroup of 23 patients and the remaining registry population was the mortality rate. Ten of the 23 patients have died, and in many cases the cause of death could be linked to the immunologic abnormality. This study establishes an association between SHML and clinically significant immune dysfunction and provides further evidence that this frequently multisystemic disease may be one manifestation of disordered immunity.

Adolescent↗

Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer.

AIMS: This prospective study was designed to determine the utility of 18F-labelled deoxyglucose (FDG) in positron emission tomography (PET) (FDG-PET) for assessing the response to neoadjuvant chemoradiation therapy (CRT) in locally advanced oesophageal tumours. PATIENTS AND METHODS: Thirty-six patients with locally advanced oesophageal cancer (clinical T4 stage) without organ metastases, underwent FDG-PET before and 1 month after CRT. Patients were classified as major responders by serial FDG-PET when the post-CRT PET demonstrated a strong reduction of FDG uptake at the primary tumour site (>80% reduction of tumour-to-liver uptake ratio) without any abnormal FDG uptake elsewhere in the body. PET response was compared with histology obtained during post-induction transthoracic oesophagectomy. RESULTS: A strong correlation was found between the extent of lymph node (LN) involvement as shown by the pre-CRT PET and the major response rate (P = 0.001): such response occurred in nine of 11 N0M0 patients (82%), in three of nine N(1-2)M0 patients (33%) and in two of 16 patients (13%) with distant lymphatic spread. Such a correlation was not found for computed tomography or endoscopic ultrasonography. The sensitivity of serial FDG-PET for a major CRT response was 10 of 14 (71%), its specificity 18 of 22 (82%). The concordance between the response assessment by PET and histopathology was 78%. The median survival time after CRT of PET major responders compared with PET non-major responders was 16.3 months and 6.4 months, respectively. The metabolic response as measured by serial FDG-PET is a stronger prognostic factor for overall survival (P = 0.002) than the extent of LN involvement seen on the pretreatment FDG-PET (P = 0.087). CONCLUSIONS: These data indicate that CRT response as assessed by serial FDG-PET is strongly correlated with pathological response and survival.

Adenocarcinoma↗

[Inguinal lymph node metastasis of seminoma 18 years after initial treatment: a case report].

Late relapse of testicular tumor is rare. We report a case of recurrence of seminoma at left inguinal lymph node 18 years after initial treatment. A 63-year-old man had a left orchiectomy for left testicular tumor (T1N0M0) in February 1985, with no past history of scrotal or inguinal surgery. Histological examination revealed seminoma (pT1), and prophylactic radiotherapy (34.2 Gy) to para-aortic and left hemi-pelvic regions was perfomed. In November 2003, the patient presented with left inguinal swelling, and was referred to our hospital with suspicion of metastasis to left inguinal lymph nodes. Serum markers (AFP, hCG, hCGbeta and LDH) were normal. Computerized tomography (CT) showed three masses in the left inguinal region, but no other abnormal mass was detected at chest, abdomen or pelvis. Lymphoidectomy of the left inguinal region was perfomed in January 2004, and the mass revealed to be metastasis of seminoma by histological examination.

Humans↗

Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice.

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28-/- MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRalphabeta+ T cells. Although levels of IgM Abs were unchanged in CD28-/- MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28-/- MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.

Animals↗

Tumours of the oropharynx and oral cavity: perineural spread and bone invasion.

Clinical examination of the oral cavity and oropharynx provides essential information in the assessment of neoplastic lesions. A precise evaluation of their deep spread along the most common growth pathways can be achieved by imaging, ranging from the basic, but nowadays incomplete, information of conventional X-ray, to the sophisticated details obtained by MR. Three oncological questions must be faced: the three dimensional evaluation of primary tumour spread; the assessment of nodal involvement; the post-treatment survey with the early detection of local recurrences, during the follow up. Either CT or MR accurately assesses the deep extension of neoplasms, nevertheless, the most cost-effective protocol is provided by a combination of CT and ultrasound (staging respectively T and N). MR is the technique of first choice when an infiltration of the base of the tongue or perineural spread is suspected, because of its superior ability to detect muscular invasion and segmental abnormalities of cranial nerves. Bone involvement can be adequately showed by MR not only because focal erosions of the cortical rim are well demonstrated, but also by means of the early demonstration of bone marrow abnormalities. Moreover, MR plays an essential role during the follow up, as it is the only morphological imaging technique permitting to differentiate recurrent tumour and necrosis from scar tissue.

Cicatrix↗