Chromosome aberrations in atypical chronic lymphocytic leukemia: a cytogenetic and interphase cytogenetic study.

To define better the chromosomal profile of atypical chronic lymphocytic leukemia (aCLL), cytogenetic and interphase cytogenetic studies were performed in 43 cases, using mitogen-stimulated cultures and DNA probes detecting the two most frequently occurring aberrations in CLL, ie +12 and 13q14 deletions. All cases showed monoclonal CD5/CD19-positive lymphocytosis, with more than 10% large lymphocytes and/or prolymphocytes in peripheral blood smears and reactivity with FMC7, or bright expression of surface immunoglobulins in a fraction of the cases. Karyotype aberrations were detected in 27 of 43 cases (62.8%). Recurrent chromosome changes were +12 (nine cases), 13q14 aberrations (five cases), 11q anomalies (three cases), 6q21-q23 abnormalities and 4q anomalies with different breakpoints (two cases each). Additional chromosome changes were seen in four cases with +12, in three cases with 13q14 anomalies, in two cases with 11q anomalies, in one case with 6q and 4q anomalies. Trisomy 12 was associated with 13q14 anomalies in three cases, one of which also had an 11q abnormality; other associations, found in one case each, were: 13q14 deletion with a 6q anomaly, 11q anomaly with 13q- and 7q-, a 6q anomaly with 7q- and +12. Interphase cytogenetics confirmed the results of chromosome banding analysis and showed that six patients with normal karyotype or no mitosis in fact had concomitant +12 and 13q14 deletion in four cases and isolated +12 or 13q14 deletion in one case each, with a resultant 76% overall incidence of cytogenetic abnormalities. The presence of +12, 13q14 deletions, 11q, and 6q21-q23 anomalies in 19 cases was associated with a 2-month median interval between diagnosis and start of treatment, as compared with a 24-month median interval in 14 cases with normal karyotype or non-recurrent chromosome changes (P = 0.003). We conclude that aCLL is characterized by a relatively high incidence of chromosome anomalies, with recurrent chromosome changes, involving chromosomes 12, 13q14, 6q21q23, 11q, and, possibly, 4q. The presence of complex karyotypes, with concomitant abnormalities of 13q, +12, 6q, 11q, suggests that the development of sequential chromosome changes, rather than any single specific anomaly, may underlie leukemogenesis in this cytologic subset of CLL, partially accounting for the relatively aggressive clinical course.

Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol.

In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P<0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.

In vitro assessment of bone marrow endothelial colonies (CFU-En) in non-Hodgkin's lymphoma patients undergoing peripheral blood stem cell transplantation.

The distribution and functional characteristics of in vitro bone marrow (BM) endothelial colonies (CFU-En) were studied in 70 non-Hodgkin's lymphoma (NHL) patients in different phases of the disease to explore the association between CFU-En growth and angiogenesis, and between the number of CFU-En and the presence of hematopoietic and mesenchymal progenitor cells. The mean number of CFU-En/10(6) BM mononuclear cells seen in remission patients was significantly higher than that seen in newly diagnosed patients (P=0.04), and in normal subjects (P=0.008). Patients with low-grade NHL in remission displayed a higher CFU-En value compared with high-grade NHL (P=0.04). In the autograft group (40 patients), a significant reduction of CFU-En number was detected in the first 4-6 months after transplantation. In remission patients, the CFU-En number positively correlated with the incidence of BM colony-forming unit granulocyte-macrophage (CFU-GM) (P=0.013) and CFU-multilineage (CFU-GEMM) hematopoietic colonies (P=0.044). These in vitro data show that CFU-En numbers increase following standard-dose chemotherapy, thus providing a rationale for further investigating the effects of different cytostatic drugs on BM endothelial cells growth and function.

Involvement of chromosomes 12 and 14 in the cutaneous stage of mycosis fungoides: cytogenetic evidence for a multistep pathogenesis of the disease.

Cytogenetic studies were performed on the cells of bone marrow, peripheral blood, and skin tumor biopsies from a patient with mycosis fungoides at an early stage. Chromosome abnormalities were detected in 100% of the cells harvested from the cutaneous specimen, whereas the cells of the bone marrow and blood were karyotypically normal. Three related clones, showing increasing cytogenetic complexity, were found. Chromosome #12 was abnormal in all metaphases, and an abnormal 14q chromosome was present in a minority of cells belonging to the most complex emerging subclone. These data, along with the findings of important signs of chromosome imbalance, suggest a polyphasic evolution of this chronic T lymphoproliferative disease.

Cytogenetically distinct leukemic cell lines displaying in vitro specific proliferative and differentiation capacities may account for early disease relapse in the blast phase of CML.

The cytogenetic features and the proliferative and differentiation capabilities of blast cell fractions purified on a density gradient were studied in one patient with chronic myeloid leukemia (CML) in blast crisis, both at the emergence and at relapse of the disease. The results show that relapse was due to the appearance of a new leukemic cell line that was characterized by peculiar chromosomal, growth, and differentiation features, which seemingly accounted for early refractoriness to therapy and disease progression.

Chromosome aberrations in CD34-positive acute myeloid leukemia. Correlation with clinicopathologic features.

Morphologic, immunologic, and cytogenetic features were studied in 30 newly diagnosed patients with CD34-positive (CD34+) de novo acute myeloid leukemia (AML) in comparison with 30 patients with CD34-negative (CD34-) AML. Karyotype at diagnosis was abnormal in 25/30 CD34+ AML patients, of which nine had major karyotype aberrations (MAKA). Clonal chromosome changes were detected in 9/30 patients with CD34- AML. The most frequent chromosome aberration in CD34+ patients was -5/5q-, an aberration showing a strong association with the M2 FAB subtype of AML. Other recurring chromosome changes involved chromosome 16q (four cases) and chromosome 17p (three cases). Total or partial monosomy 7q was detected in three cases. Among CD34- AML, two patients had the classical t(15;17) and two had structural aberrations of 6q. Among patients with CD34+ AML, nine had MAKA in association with trilineage myelodysplasia (TMDS). TMDS was infrequent in CD34+ AML without MAKA and in CD34- AML. Complete remission (CR) was achieved in 8/30 CD34+ AML (26%), as compared with 22/30 CD34- AML (73%), and median survival was 2 months in the former group and 8 months in the latter. No patient with CD34+ AML and MAKA achieved CR, whereas 8/21 CD34+ AML without complex chromosome changes or with normal karyotype achieved CR. In conclusion, a distinct cytogenetic profile may be associated with CD34+ AML. Cytogenetic findings in CD34+ AML may be clinically relevant in that they may disclose a subset of patients with MAKA with a low CR rate.

Alpha interferon in T helper phenotype chronic lymphocytic leukemia: a report of three cases.

Three patients affected by T helper chronic lymphocytic leukemia were treated with low dose interferon alpha-2b (3 MU/m2 3 times weekly). The disease presented different pathologic expressions with diffuse skin lesions in one patient, a mild clinical course and a prolymphocytic variant with aggressive features, respectively, in the other two cases. A consistent response was observed within 3-6 weeks; by that time a reduction of blood and marrow lymphocytosis in the three patients and a regression of the cutaneous lesions were documented. Therefore, it should be emphasized that the use of alpha IFN, whose effectiveness on cutaneous T cell lymphomas has been already demonstrated, may represent an active agent in the treatment of leukemic T helper phenotype chronic lymphocytic proliferations.

[Skeletal changes in non-Hodgkin lymphoma]. / Le alterazioni scheletriche nei linfomi non-Hodgkin.

140 patients affected by non-Hodgkin lymphoma (NHL) are performed by the A. Skeletal involvement of metastatic nature is observed in 14 of these (10%). Only the aggressive lymphomas have radiographic bone disseminations. At beginning of disease no patient has interested by bone changes. The most frequent roentgenographic finding observed by the A. include high incidence of osteolityc lesions: in particularly, pattern so called "permeative" is present in 35.6% of cases. Osteosclerotic and mixed manifestations were much less commonly observed (7,2% respectively). Periosteal reactions is not observed in any cases. The value of roentgen skeletal investigation in diagnosis, staging and therapy of NHL is discussed by the A.

[Value and limits of echography and abdominal lymphography in malignant lymphomas]. / Valori e limiti dell'ecografia e della linfografia addominale nei linfomi maligni.

Diagnostic results obtained by echography and lymphography in the study of abdominal lymphoglandular involvement in patients with lymphomas are compared. The data indicate that while lymphography is more revealing, the two examinations should be used together in staging. Echography, on the other hand, should be used for long-term surveillance, once the lymphographic contrast medium has been absorbed.

A case of disseminated Langerhans' cell histiocytosis treated with thalidomide.

Tumor necrosis factor alpha (TNF-alpha) seems to play a key role in the pathogenesis of Langerhans' cell histiocytosis (LCH). Thalidomide is an immunomodulator agent of inflammatory cytokines including TNF-alpha. To our knowledge this is the first case of disseminated LCH successfully treated with thalidomide.

[Plasma cell dyscrasias and diffuse idiopathic skeletal hyperostosis. Is it a merely accidental association?]. / Discrasie plasmacellulari ed iperostosi scheletrica idiopatica diffusa. Associazione puramente casuale?

The radiologic staging of a series of 144 patients (88 males and 56 females) affected with plasma-cell dyscrasias and observed over a 26-month period, revealed both the well-known bone myeloma-related abnormalities and hyperostotic lesions similar to those described in diffuse idiopathic skeletal hyperostosis. The incidence of skeletal hyperostosis was 31.94%, much higher than that reported in literature for the general population (5%). Typically, the axial skeleton is the most common location for abnormalities in multiple myeloma (MM) as well as in DISH: involvement of the dorsal spine was observed in 65% of cases, the cervical spine was involved in 34.8% of patients, and the lumbar spine in 28.3%. Peripheral ossifying enthesopathy, considered as "whiskering" in the pelvis, was found in 12 cases (8.2%), 7 males and 5 females. DISH was indifferently present in both MM (23 cases), with severe osteolysis (stage III) or simple osteoporosis (stage I), and monoclonal gammopathy of undetermined significance (MGUS) (17 cases), usually without any myeloma-related bone lesions, and in Waldenström disease (4 cases). Many hypotheses are discussed as to the possible pathogenesis (e.g.: accidental, dysmetabolic, or degenerative) of hyperostosis in dysgammaglobulinemias, but, to date, they are no more than mere guesses. DISH is a disorder the etiology of which is still unknown: it is likely to be an ossifying diathesis, but its incidence in both illnesses--which are both plasma-cell dyscarsias--is too high for the association to be accidental. Thus, a pathogenetic factor produced by multiple myeloma can be hypothesized, capable of increasing the so-called idiopathic hyperostosis.

[Non-hodgkin's lymphomas of extranodal localization. Strategies for imaging diagnosis]. / I linfomi non Hodgkin con localizzazione extranodale. Strategia della diagnostica per immagini.

PURPOSE: To evaluate the diagnostic workup proposed by the UICC (International Union against Cancer) Flow charts for diagnosis and staging of lymphomas in developed and developing countries (1998). MATERIAL AND METHODS: Our series consists of 134 patients with early non-Hodgkin's lymphoma (NHL). The patients, 75 men (56%) and 59 women (44%), ranging in age 14-80 years (mean: 56.8), were examined with chest radiography and thoracoabdominal CT. Abdominal US was used only in the follow-up of low-grade NHL. The patients were classified according to the Working Formulation criteria (1981) and staged as proposed by the Ann Arbor Conference guidelines (1971). RESULTS: At diagnosis, 5 patients (3.7%) were in stage I, 32 (23.8%) in stage II, 46 (34%) in stage III and 51 (38%) in stage IV. Extranodal involvement was seen in 59 patients (44%), which was present at disease onset in 49 of them (80%) and developed later on in 10 (20%). Gastrointestinal tract and respiratory system were the most frequent sites of extranodal involvement (15 cases, 25%), followed by liver (12%), genitourinary system (including the ovary), adrenal glands, the craniocervical region, muscles and finally the breast. The parotid gland, thyroid and bone were involved in one case only each. DISCUSSION AND CONCLUSION: In agreement with previous literature reports, our study confirms that the best technique currently available for diagnosis, staging and follow-up of malignant lymphoma is chest-abdomen CT. Indeed, even though extranodal involvement exhibits extremely variable patterns, there are some typical findings at CT, such as homogenous structural hypodensity, low contrast enhancement, frequent plurivisceral involvement and/or local lymph node involvement. Our study followed the 1998 UICC guidelines for cancer diagnosis and staging in developed countries, based on the histology of lymph node biopsy material and on imaging techniques such as CT, MRI and PET. As for developing countries, lymph node biopsy is the most easily available, and thus preferred, examination, while imaging diagnosis features chest radiography and abdominal US.

Bone marrow imaging in plasma cell dyscrasias: review of 130 cases.

Skeletal radiography, bone and bone marrow scintigraphy have been performed in 130 patients with plasma cell dyscrasias (119 multiple myeloma, 9 MGUS and 2 Waldenström disease). Our results confirm: 1) that radiography is much more sensitive than scintigraphy in the identification of the lesions typical of myeloma, but in the first stage bone scintigraphy and especially bone marrow scintigraphy are more sensitive than x-ray for the detection of regions affected by focal lesions; 2) that bone scintigraphy is of particular value in detecting some abnormalities in specific sites not fully visualized by x-ray; 3) that bone marrow scintigraphy is a valuable diagnostic tool in the early stage of myeloma, especially for evaluating the progression of the disease, because it is able to demonstrate not only focal lesions, but also bone marrow expansion. We believe that bone marrow scintigraphy may be a useful technique in the early diagnosis and follow-up of multiple myeloma, particularly in the detection of unusual forms (i.e., "smouldering" myeloma), but it remains only an "additional" technique for bone imaging.

Acute myelomomocytic leukemia terminating in histiocytic medullary reticulosis: cytochemical, cytogenetic and electron microscopic studies.

A case of acute myelomonocytic leukemia terminating in histiocytic medullary reticulosis is reported. The evolution of a single cellular clone presenting with progressive change of the morphological features of the leukemic cells towards more anaplastic elements endowed with prominent phagocytic properties is suggested on the basis of both cytochemical and chromosomal data. The histiocytic nature of the malignant proliferating cells and platelet phagocytosis has been confirmed by electron microscopic investigation. The main pathogenetic explanations of the evolutionary patterns of the disease are discussed with relation to: a) involvement of a common stem cell giving rise to different proliferative patterns of cells in a multiphasic sequence; b) release of dysplastic platelets and defective erythrocytes with massive sequestration by histioid phagocytic cells; and c) coexistence of two different disorders.

[Role of computerized tomography in the diagnosis of bone disease in multiple myeloma]. / Ruolo della tomografia computerizzata nella diagnosi della malattia ossea del mieloma multiplo.

PURPOSE: To assess the role of CT in the diagnosis and management of multiple myeloma (MM) and to investigate if CT findings can influence the clinical approach, prognosis and treatment. STUDY DESIGN AND PATIENTS: We reviewed the findings relative to 273 MM patients submitted to CT June, 1994, to December, 1996. The patients were 143 men and 130 women (mean age: 65 years): 143 were stage I, 38 stage II and 92 stage III according to Durie and Salmon's clinical classification. All patients were submitted to blood tests, spinal radiography and CT, the latter with serial 5-mm scans on several vertebral bodies. The CT unit was a Philips Tomoscan SR 7000. RESULTS: CT showed lysis foci in some vertebral bodies (4 cases) where conventional radiography had shown only aspecific osteopenia. CT also depicted vertebral arch and process involvement in 3 cases with the vertebral pedicle sign. Moreover, CT proved superior to radiography in showing the spread of myelomatous masses into the soft tissues in a case with solitary permeative lesion in the left pubic bone, which facilitated subsequent biopsy. As for extraosseous localizations, CT demonstrated thoracic soft tissue (1 woman) and pelvic (1 man) involvement by myelomatous masses penetrating into surrounding tissues. In our series, only a case of osteosclerotic bone myeloma was observed in the pelvis, associated with lytic abnormalities. DISCUSSION AND CONCLUSIONS: The role of CT in the diagnosis and management of MM has not been assessed, because this technique demonstrates tumor extent more accurately than radiography but CT findings do not seem to improve the clinical approach and therapeutic management of the disease. Nevertheless, we recommend CT for some myelomatous conditions, namely: a) in the patients with focal bone pain but normal skeletal radiographs; b) in the patients with M protein, bone marrow plasmocytosis and back pain, but with an inconclusive MM diagnosis; c) to assess bone spread in the regions which are anatomically complex or difficult to study with radiography and to depict soft tissue involvement; d) for bone biopsy.

[Secondary non-Hodgkin's lymphoma of the small intestine. Double-contrast radiological study using oral enema]. / I linfomi non-Hodgkin secondari dell'intestino tenue. Studio radiologico a "doppio contrasto" mediante clisma transbuccale.

The small bowel double contrast enema was performed in 44 patients with diffuse non-Hodgkin lymphoma. "Secondary" involvement of small bowel is detected in 14 subjects (31.8%), but radiographic features are not specific for the disease. Really, lymphoma and regional enteritis may demonstrate strikingly similar patterns. The signs we have considered are: intraluminal involvement, with narrowing or dilated segments; diffuse or localized polypoid lesions; large extraluminal masses. The roentgenographic pattern of the mucosal folds consists of thick, straight or tortuous folds, with "cogwheel" appearance and moderate dilatation of the lumen.

[Bone disease in multiple myeloma. A study of 237 cases]. / La malattia ossea nel mieloma multiplo. Studio di 237 casi.

From 1984 to 1990 the authors reviewed the radiologic-clinical charts of 237 patients affected with multiple myeloma (MM). The series included 127 males and 110 females (mean age: 66 years) who had been classified according to Durie and Salmon clinical criteria. All the patients underwent X-rays of the skeleton, as recommended in international literature; moreover, 148 subjects underwent whole-body bone scintigraphy, and 130 bone marrow scintigraphy. A selected group of cases (18 male/female patients) were submitted to bone densitometry employing both quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA). The results follow: 1) in the first stage of the disease, a high number of patients (29.5%) exhibits no skeletal abnormalities on X-rays; the most common lesion locations include the spine (49%), skull (35%), pelvis (34%), ribs (33%), humeri (22%), femora (13%) and mandible (10%); 2) the most frequent pattern is osteolysis, as a characteristic "punched-out" multiple lesion; the second most frequent lesion is osteopenia (43%), especially in the spine; pathologic fractures are common (54%) in the ribs, vertebral bodies, limbs; typical associations of features and sites are seen on X-ray images, which sometime make diagnosis easier; 3) whole-body scintigraphy, revealing aspecific uptake only in the presence of pathological fractures, is not recommended in the first staging of the disease, but is considered as a valuable technique in the follow-up, when the patients become symptomatic; 4) bone marrow scintigraphy, especially in the "marrow expansion" pattern, might be considered as an attempt made by the body to recover the central space which was destroyed by myelomatous involvement. The prognostic value of this technique is still to be assessed; 5) bone densitometry, by confirming the grade of osteopenia, reveals that osteoporosis is a peculiar pattern of bone disease in MM, which is not related to age only; 6) conventional radiography of the skeleton is the method of choice in the diagnosis of lytic areas of MM, and remains, as yet, irreplaceable. The other diagnostic techniques--i.e., CT and MRI--can be used to evaluate the extent of bone and soft tissue involvement, in the cases with questionable diagnosis, and to assess the degree of marrow involvement.