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Clinical and histopathologic findings were reviewed in 57 cases in which there had been a diagnosis or suspicion of malignant lymphoma in the skin other than mycosis fungoides. Patients were included only if 1) extracutaneous tissue satisfactory for lymphoma classification was available, or 2) there was no evidence of extracutaneous involvement after a minimum of five years. Thirty-five patients had systemic lymphoma; in eight of these that disease first became manifest in the skin. There were two patients with typical lymphomatoid papulosis and one with a somewhat similar but solitary lesion which did not recur after excision; we have termed the latter a "solitary lymphomatoid papule." The remaining 19 cases without extracutaneous involvement were regarded as benign lymphoid hyperplasia. Clinically, the cutaneous lesions of malignant lymphoma were difficult to distinguish from those of lymphoid hyperplasia; only lymphomatoid papulosis was distinctive. Histologically, it was found that a definite diagnosis of malignant lymphoma (other than mycosis fungoides) could be made in the skin when three criteria were fulfilled: 1) exclusive presence or marked preponderance of medium-sized or larger lymphocytes, 2) absence of preferential involvement of the upper dermis, and 3) absence of extensive epidermal infiltration. These criteria were met in 21 cases of lymphoma. In both cases of lymphomatoid papulosis, the infiltrate was predominantly composed of large lymphocytes but was primarily limited to the upper dermis. The "solitary lymphomatoid papule" contained a similar cell population and involved the full thickness of the dermis; however, it displayed a prominent intraepidermal component. Fourteen cases of malignant lymphoma and all cases of lymphoid hyperplasia were characterized by a mixture of lymphocytes of varying size or a predominance of small lymphocytes. Nine cases of lymphoid hyperplasia exhibited at least one of three findings not observed in lymphoma; these findings were 1) germinal centers, 2) marked paucity of medium-sized lymphocytes in comparison to both small and large lymphocytes, and 3) sharp margination between adjacent groups of small and large lymphocytes. Aside from one case of small lymphocytic lymphoma which showed deep subcutaneous extension, the remaining cases (13 malignant and 10 benign) could not be reliably differentiated from each other by skin biopsy findings alone and were thus considered histologically indeterminate. The 13 lymphoma cases in this group were all of the small lymphocytic or follicular types; the failure of follicular lymphoma to exhibit a follicular pattern in the skin was a major impediment to its recognition in that location. The cutaneous infiltrates in all cases of large lymphocytic, Burkitt's, and lymphoblastic lymphoma were diagnostic of malignancy.
A p53 C-terminal peptide (aa 361-382, p53p), fused at its C-terminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The mechanism of cell death by p53p-Ant was through the FADD/caspase-8-dependent pathway without the involvement of the TRAIL pathway, Bcl-2 family and cell cycle changes. Blocking Fas with antibody did not alter the peptide's effect, suggesting that Fas itself did not interact with the peptide. Transfection with a dominant-negative FADD with a deleted N-terminus inhibited p53p-Ant-induced apoptosis. Its mechanism of action is related to the FADD-induced pathway without restoration of other p53 functions. p53p-Ant is a novel anticancer agent with unique selectivity for human cancer cells and could be useful as a prototype for the development of new anti-cancer agents.
Meningiomas are relatively common (22%) vascular brain tumors. 3-11% of meningiomas are malignant, and defy currently available therapy. Inhibition of neovascularization is one potential strategy for treating these hypervascular tumors. Inhibition of tumor-induced angiogenesis by TNP-470 (previously termed AGM-1470), a synthetic analogue of fumagillin, was tested on the growth of human non-malignant and malignant meningiomas in nude mice. TNP-470 significantly inhibited tumor neovascularization and tumor growth of both non-malignant and malignant meningiomas. TNP-470 is now in human trial and should be tested for efficacy in treating malignant or recurrent aggressive meningiomas.
Cutaneous findings often reflect the presence and course of an internal disease. Recognition of external clues is important to facilitate both early diagnosis and prompt treatment of the internal disorder. Early recognition is especially valuable in a patient with an internal malignant disease because intervention may significantly affect survival. In this two-part series, we review the spectrum of cutaneous markers of internal malignancy. Part I focuses on malignant involvement of the skin caused by either direct extension or metastases and the genodermatoses with malignant potential. Part II will be devoted to the paraneoplastic skin manifestations of internal malignancy as well as environmental carcinogens that produce cutaneous features. We also discuss some proposed but controversial associations between skin disease and internal malignancy.
Concentration of metallothionein in the malignant and non-malignant tissues of the human liver was determined by the Cd-hem method. The concentration of metallothionein was high in the non-malignant tissue (471 +/- 306 micrograms/g). Metallothionein in the non-malignant tissue was mainly Zn-thionein and metallothionein-bound Zn was a major chemical form of Zn in the non-malignant tissue. The concentration of metallothionein in the malignant tissue was 75.6 +/- 79.6 micrograms/g, and significantly lower than that in the nonmalignant tissue. A strong, positive relationship was observed between the Zn and metallothionein concentrations, and the regression equation was MT (microgram/g) = -94.7 + 11.9 Zn (micrograms/g).
The incidence and sites of metachronous malignancies were retrospectively determined from the records of 763 patients seen at Yale University medical Center and affiliated hospitals with previously untreated, invasive carcinoma of the uterine cervix from 1953-1972. These patients were treated predominantly with radiation therapy; follow-up status was known for periods of 5-25 years or until time of death in over 96% of the patients. Forty-four patients had second malignancies noted at least 6 months after the initial cervical cancer was diagnosed. The expected incidence of second malignancies was determined from the Connecticut State Tumor Registry data controlling for year of diagnosis of the cervical cancer, patient age, sex, and time at risk (person-years exposure). To correct for any error in estimation of second malignancies introduced by the existence of a latency period for the development of a second cancer, the expected incidence of malignancies was also computed for 5-year time intervals following the cervical cancer. No significant increase in second malignancies was found (observed/expected-44/36) for the entire follow-up period nor for any individual 5-year interval. However, a statistically significant increase in lung cancer and vulva-vaginal cancer was noted and a significant decrease in breast cancer was observed. Cox regression analyses were performed to study the effect of total radium exposure and total external beam treatment, adjusting for other factors. No statistically significant increased risks were found.
The clinical records and histologic materials from 7 cases with malignant lymphoma (ML) in the nose were examined, and the results were compared to those in malignant histiocytosis (MH) presenting as lethal midline granuloma previously reported by us. The main differences in the clinical findings were 1) younger initiation of the disease in MH than in ML (mean values were 56 and 37 years of age, respectively); 2) ML showed a polypoid nasal mass with necrosis but MH showed necrotic granulomatous lesions; and 3) much better survival in ML than in MH. The histological findings of malignant lymphoma differed from malignant histiocytosis not only in monotony but also in cytologic details. Alpha-naphthyl acetate and butyrate esterase reactions gave clear distinction between the two diseases. From these findings, we conclude that malignant lymphoma should be clinicopathologically separated from malignant histiocytosis.
Primary cultures of stromal cells from non-malignant and malignant breast tissues contained myofibroblasts based on immunoreactivity to alpha-smooth muscle (alpha-sm) actin. The proportions of these cells were variable among cultures from non-malignant origin while consistently high in cultures from carcinomas. High expression of ED-B fibronectin and of type V collagen was observed in myofibroblast-containing cultures. While cells from non-malignant tissues grew relatively steadily, the proliferation of carcinoma-derived cells declined during serial subculturing. In both types of cultures, alpha-sm actin and ED-B fibronectin expression decreased with increasing passage numbers. Epidermal growth factor (EGF), fibroblast growth factor b (FGFb), transforming growth factor alpha (TGF alpha) and platelet-derived growth factor (PDGF) showed consistent mitogenic effects. Addition of FGFb prolonged culture growth and allowed alpha-sm actin and ED-B fibronectin expression to persist. These results demonstrate similar phenotypic modulations in stromal cells from non-malignant and malignant breast tissues that may reflect a common stromal response to various tissue injuries, including neoplasia.
Glutathione S-transferase (GST) isoenzyme composition, isoenzyme quantities and enzymatic activity were investigated in benign (n = 4) ovarian tumours and malignant ovarian tumours, before (n = 20) and after (n = 16) chemotherapy. Enzymatic activity of GST in cytosols was measured by determining 1-chloro-2,4-dinitrobenzene conjugation with glutathione, cytosolic GST subunits were determined by wide pore reversed phase HPLC, using a S-hexylglutathione-agarose affinity column, and isoelectric focussing. Both GST activity and GST pi amount were not related to histopathologic type, differentiation grade, or tumour volume index in untreated malignant tumours. GST isoenzyme patterns were identical in benign tumours and malignant tumours before and after platinum/cyclophosphamide chemotherapy, while GST pi was the predominant transferase. Mean GST activity and GST pi amount were decreased (P < 0.05) in malignant ovarian tumours after platinum/cyclophosphamide chemotherapy compared to untreated ovarian malignant tumours. No relation was found in untreated ovarian tumours between GST pi amount and response to platinum/cyclophosphamide chemotherapy. Thus, within the limitations of the current study no arguments were found for a role of GST in in vivo drug resistance of malignant ovarian tumours to platinum/cyclophosphamide chemotherapy.
AIMS: We report two cases of secondary malignant giant-cell tumour occurring without irradiation therapy. To elucidate the mechanism of malignant transformation in this tumour, we searched for the molecular abnormalities of p53, MDM2 and the H-ras genes. METHODS AND RESULTS: These cases were retrieved after a review of 103 cases of primary giant-cell tumour of bone, registered in our institute. One case occurred in the distal femur of a 42-year-old female after surgical curettage, while the other arose in the acetabulum of a 25-year-old male after en bloc resection. Microscopically, the malignant tumour in the distal femur was composed of a proliferation of ovoid or fusiform cells arranged in fascicles with high mitotic activities. The malignant transformed tumour in the acetabulum was made up of pleomorphic tumour cells with atypical mitoses. In the tumour of the distal femur, both p53 and H-ras mutations were detected. Abnormal nuclear accumulation of p53 protein and c-myc expression were also revealed by immunohistochemistry. In both cases, the recurrent malignant tumour over-expressed MMP-9 and revealed a higher MIB-1-labelling index compared with the primary conventional giant-cell tumour. CONCLUSIONS: Our results suggest that multiple oncogene or tumour suppressor gene mutations may play an important role during malignant transformation in conventional giant-cell tumours.
AIMS: The UK National Health Service Breast Screening Programme has proposed five categories for reporting breast needle core biopsies. The majority of cores are reported as benign (B1), normal (B2) or malignant (B5). The predictive value of the two borderline categories suspicious of malignancy (B4) and lesion of uncertain malignant potential (B3) was studied. METHODS AND RESULTS: Over a 2-year period a total of 3822 breast needle core biopsies were performed, with 2997 from symptomatic patients and 825 from women undergoing mammographic screening, including 43 B4 reports (40 patients) and 120 B3 reports (116 lesions in 115 patients). The frequencies of B4 (2.5% versus 0.7%) and B3 cores (7.3% versus 2.0%) were both higher in screening than in symptomatic patients. B4 was most commonly used for small fragments of atypical cells separate from the main core or focal atypical intraductal proliferations. The criteria for calling a core B3 were: atypical intraductal epithelial proliferations (including foci that in excision specimens would be classified as atypical ductal hyperplasia), lobular neoplasia, radial scar, papillary lesion, fibroepithelial lesion with cellular stroma and spindle cell proliferations. Excision biopsies were performed in 39 patients with B4 core and 96 with B3 core. Invasive carcinoma or ductal carcinoma in situ was seen in 33 of the patients with B4 (85%) and in 29 of those with B3 cores (25%). Some categories of B3 core were associated with a higher rate of malignancy (40% for atypical intraductal epithelial proliferations and 46% for lobular neoplasia). CONCLUSIONS: The positive predictive value for carcinoma is high following a B4 core (86%). The lesion should be excised, but definitive cancer treatment is not appropriate. In some cases a definite diagnosis of malignancy can be made on repeat core. The B3 group is more heterogeneous and has a lower rate of malignancy on further biopsy (25%). The majority of B3 lesions require excision. All these patients should be discussed at multidisciplinary meetings.
Barrett's esophagus, which is histologically characterized by metaplastic columnar epithelium, is a common condition observed in approximately 10-20% of patients with gastroesophageal reflux disease. These lesions can typically progress from metaplasia with atypia to low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. It is of great clinical importance to correctly grade these lesions and to identify changes with a high risk of malignant transformation, inasmuch as high-grade dysplasias and early adenocarcinomas in patients with Barrett's esophagus have a high chance for cure. The identification of high-risk lesions in Barrett's esophagus by histologic evaluation has drawbacks, especially regarding sampling errors and frequent intra- and interobserver discrepancies in the histopathologic grading/staging of these lesions. Immunostaining with a variety of antibodies provides a better understanding of the process of malignant transformation and helps to identify early markers of malignant transformation in Barrett's esophagus lesions. In this review, we will summarize the current knowledge about the value of immunostaining in the diagnosis of malignant and non-malignant Barrett's epithelium and its role to better define lesions with high risk for malignancy in this disorder.
AIM: To evaluate the benefit of echo-contrast-enhanced Doppler sonography in the differentiation of benign vs. malignant breast lesions after surgical removal of a malignant breast mass. METHODS: Thirty-eight patients referred for biopsy of a palpable, suspicious scar lesion 1-15 years (mean 3.3 years) after surgery for breast cancer were examined. During baseline ultrasound examination a subjective scoring system of the vascularity, the number, the regularity of vessels' course and their Doppler parameters were assessed. After injection of an ultrasound contrast agent (Levovist) the same scoring system was applied to the parameters together with enhancement kinetics, enhancement intensity and enhancement pattern. Any increase in the scoring level of two or more characteristics (vascularity, number of vessels, intensity of enhancement in the tumor or regularity score of vessels in the lesion) was defined as suspicious for malignancy. A marked increase of enhancement in the immediate tumor periphery was also regarded as suspicious for malignancy. The sonographic results were assessed prospectively and correlated with the histology of the lesion. RESULTS: Of the 38 patients with a clinically-suspicious scar lesion, there were 28 true scars and 10 malignant scar lesions. All scar lesions showed no or slight vascularity on baseline sonography. After Echocontrast-enhancement a significant increase in tumor vascularity and the number of tumor vessels could be demonstrated in all 10 malignant lesions but in only one of the 28 benign scars. CONCLUSION: Scars pose inherent technical problems for optimal mammography. Sonographic evaluation of the vascularity of the lesion with contrast enhancing agents showed improved diagnostic accuracy in the hands of an experienced examiner.
The experiments reported in this study were designed to examine the question of whether a mammary epithelial cell's independence from hormonal requirements is established at the time of carcinogenic initiation, or whether the emergence of hormone independence is associated with the process of tumor progression. A newly developed rat model of mammary carcinogenesis was used in which the latency period to lesion detection is very short and in which the frequencies of both pre-malignant and malignant mammary lesions can be quantified. Two experiments were conducted in Sprague-Dawley rats injected with 50 mg MNU/kg body wt at 21 days of age. In the first experiment 47 animals were ovariectomized after the detection of a mammary tumor of palpable size. Forty-six of the 47 tumors assessed, all of which were subsequently classified as mammary gland adenocarcinomas, regressed to <50% of their initial volume within 14 days of bilateral ovariectomy. However, both pre-malignant and malignant mammary gland lesions were observed when animals were killed. In Experiment 2 a total of 60 rats were ovariectomized 7 days after MNU was injected. At 35 days post carcinogen ovariectomized animals had a higher incidence of intraductal proliferations than sham-operated controls (P = 0.03); there was no effect of ovariectomy on the incidence of ductal carcinoma in situ or carcinoma. The multiplicity of intraductal proliferations was increased by 58% in ovariectomized rats (P = 0.12), but the number of mammary carcinoma per rat was reduced (3.8 vs. 1.57, P = 0.02). These data are consistent with the hypotheses that the progression of pre-malignant to malignant lesions is inhibited in the mammary gland by ovariectomy and that the hormone independent phenotype can be conferred at the time of carcinogenic initiation.
Malignant pigmented villonodular synovitis (PVNS) is a rare lesion whose existence may be debatable. We studied eight cases that we consider to be examples of malignant PVNS. The three male and five female patients were aged 12 to 79 years. The knee was involved in three cases; the ankle in two; and the cheek, dorsum of the foot, and thigh in one each. Four patients had swelling for 6 months to 17 years before presentation. Three cases of malignant PVNS were secondary, arising in patients in whom PVNS had been documented previously, and five cases were primary, with histologic features similar to those of the secondary ones. Important histologic features of malignancy were (a) a nodular, solid infiltrative pattern of the lesion; (b) large, plump, round or oval cells with deep eosino philic cytoplasm and indistinct borders; (c) large nuclei with prominent nucleoli; and (d) necrotic areas. Atypical mitoses were occasionally seen. Four patients died with pulmonary metastasis (two also had metastasis to inguinal lymph nodes). Four patients are alive from 3 1/2 to 5 years after the last surgical treatment. The malignant nature of this lesion, the histologic architecture similar to that of PVNS, and the fibrohistiocytic appearance of the cells suggest that malignant PVNS is an entity.