Small Cleaved Cell Type Research Articles

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INTRODUCTION: Lymphomas are heterogeneous group of malignant lympho- proliferative disorders. Broadly categorized into Non-Hodgkin's lymphoma (NHLs) and Hodgkin's lymphoma (HL). Decades back one of the challenging topics in morphologic pathology was accurate diagnosis and classification of lymphoma. Studies on lymphoma with clinicopathologic correlation were found to be much significant. STUDY OBJECTIVES: This was a retrospective study aimed to describe lymphomas on histo morphology and thus classify NHLs using working formulation for clinical usage (1982) and HL using Rye (1966) classification respectively. To attempt clinicopathologic correlation. METHODS: The study was done in the department of pathology, Mahadevappa Rampure Medical College, Gulbarga during the period 1989-1999. Formalin fixed paraffin wax embedded tissue blocks previously diagnosed as lymphomas in the department were used. Morphologic details by light microscopy on haematoxylin and eosin (H&E) stained sections were noted. Clinical history of each case were analysed from hospital records. Clinical and pathologic correlation was done. Special stains Reticulin (Gomori) and Periodic acid Schiff's stain (PAS) was done in relevant cases. RESULTS: Study of total 102 cases of lymphoma it was observed NHLs formed 70 cases with an incidence of 68.3%. HL accounted for 32 cases with incidence of 37.2%. NHLs commonly presented in fifth decade 24.2%, followed by fourth and sixth decade. Sex distribution showed Male: Female ratio as 2.5:1. Majority of cases presented with cervical and axillary lymphadenopathy at 41% and 20% respectively. The most frequent grade was clinically aggressive intermediate grade NHLs seen in 80% of all cases. 20 cases of NHLs were of extranodal in origin. The most common site was gastrointestinal tract (60%) and head and neck region with (30%). The major histologic type in both nodal and extranodal NHLs was diffuse small cleaved cell type (DSCC). HL showed sex ratio of 1.8:1.The common age group was in third and second decade. Mixed cellularity was most frequent type. No extranodal HL was noted. CONCLUSION: This study confirmed the usefulness of histomorphology in diagnosis of lymphomas and its basis used in the classification systems. Clinicopathologic correlation was significant. The Result was comparable with various author study series. A relook into the still clinical usefulness of the above classification system in this

Co-Activation of HOXB7 and BCL2/MYC Via Biallelic IGH Rearrangements in a B-Cell Lymphoma Cell Line.

Homeobox (Hox) genes mediate tissue-specific expression during development where dysregulation may provoke neoplasia and the involvement of specific Hox genes in hematopoietic malignancies is a recurring theme. In B-cell neoplasias dysregulation may be effected by juxtaposition of Hox genes with immunoglobulin gene regulatory elements, notably IGH. We describe the molecular cytogenetic analysis of a cell line (Epstein-Barr virus negative) established from ascites fluid taken from a 67-year-old male patient at diagnosis of B-cell non-Hodgkin's lymphoma (follicular, small cleaved cell type). The cell line carries a complex t(8;14;18)(q24;q32;q21) leading to activation of both MYC (at 8q24) and BCL2 (at 18q21) via juxtaposition with different enhancer regions of the IGH locus at 14q32. Both translocated alleles of MYC and BCL2 showed additional genomic amplification in conjunction with IGH by formation of an homogeneously staining region on the der(8). Interestingly, the IGH allele on the second chromosome 14 homolog had also undergone chromosomal juxtaposition, this time with a breakpoint at the HOXB cluster at 17q21 leading to transcriptional activation of HOXB7 but of no other HOXB gene. Although its deregulated expression has been described in certain solid tumor subtypes, notably malignant melanoma, this is the first report describing the involvement of HOXB7 in hematopoietic malignancy. Moreover, the cell line carries a novel internal duplication of chromosome 3, dup(3)(q21q27), effecting fusion of BCL6 with MBNL1, a triplet-expansion repeat gene preferentially expressed during hematopoiesis. Our data thus identify a cell line resource modelling novel hematopoietic rearrangements, notably HOXB7 - an attractive candidate target of recurrent 17q2 rearrangements in B-cell lymphoma.

4521 Clinicopathological features of malignant lymphoma discovered by colonoscopy: an analysis according to the endoscopic classification.

Background and Aims: There have been only a few endoscopic studies with respect to primary ileocolonic lymphomas. The aims of this study were to classify these lesions according to the colonoscopic findings and to reveal the clinicopathological relationship according to the classes. Methods: Subjects were 24 cases of primary malignant lymphoma of the terminal ileum and colon which were diagnosed by colonoscopy at Asan Medical Center in the past 10 years. There were 17 men and 7 women, with a median age of 54.5 years (range, 29-75 years). We evaluated the clinicopathological features according to their endoscopic findings. Results: The chief complaints of the patients were abdominal pain (16 cases, 56%), bleeding (5 cases, 18%), and abdominal mass (4 cases, 14%). Twenty six lesions from 22 patients were endoscopically classified as follows: fungating (10 lesions, 38%), ulcerofungating (7 lesions, 27%), infiltrative (5 lesions, 19%), ulceroinfiltrative (3 lesions, 12%), and ulcerative (1 lesion, 4%). The other 2 patients were excluded from the endoscopic classification, since they had the special type, multiple lymphomatous polyposis, which involved the whole gastrointestinal tract diffusely. The location of the lesions other than multiple lymphomatous polyposis was the terminal ileum in 11 lesions (42%), the colon in 10 lesions (39%), and both regions in 5 lesions (19%). Within the large bowel, the cecum was involved most frequently, followed by the ascending colon: 6 in cecum, 3 in ascending colon, and 3 in both cecum and ascending colon. The other 3 lesions were located in the transverse colon (1), sigmoid colon (1), and rectum (1). The pathological studies revealed the diffuse large cell type in 13 cases, the large cell immunoblastic type in 5 cases, the diffuse small cleaved cell type in 3 cases, and the follicular, predominantly large cell type, and the diffuse mixed, small and large cell type in the remainder. There was no relationship between the endoscopic findings and the histologic types. Eight cases (33%) were manifested as intussusception. All of them had the fungating type in the endoscopic classification. Conclusions: Primary ileocolonic lymphomas can be classified endoscopically into the fungating, ulcerative, infiltrative, ulcerofungating, and ulceroinfiltrative types. Among the types, fungating and ulcerofungating types are the most frequent. Intussusception is a common finding in ileocolonic lymphomas and occurs mainly in the fungating type.

Prognostic factors and a predictive model of follicular lymphoma: a 25-year study at a single institution in Japan.

The incidence of follicular lymphoma in Japan is far lower than that in western countries, and no large-scale clinicopathologic studies on this neoplasm have been conducted in Japan. We reviewed histopathological specimens from 118 of 135 patients who had been diagnosed as having follicular lymphoma between 1968 and 1993. Prognostic factors influencing survival were analyzed using univariate and multivariate analyses. Factors that were independently significant upon multivariate analysis were incorporated into a predictive model. Ninety-three patients (78.8%) had a confirmed diagnosis of follicular lymphoma. Twenty-one of the remaining 25 patients were categorized as having other lymphoma subtypes, and four patients showed indefinite findings or those suggesting diseases other than lymphoma. Major characteristics of the 93 patients with follicular lymphoma were a median age of 53 years (20-85); 59 males (63%) and 34 females (37%); small cleaved cell type in 33 (35%), mixed cell type in 41 (44%) and large cell type in 19 (20%); stage I/II in 41 (44%) and stage III/IV in 50 (54%). Overall survival was 71% at 5 years, 58% at 10 years, and 43% at 15 years with a median survival of 13.3 years. Multivariate analysis revealed that two variables, age (>60) (P=0.001) and the serum LDH level (>1 x normal value) (P=0.026), were unfavorably significant prognostic factors influencing survival. The predictive model using these two variables identified three risk groups with estimated five-year survival rates of 88.5%, 56.8%, and 31.5%. Age and serum LDH were significant predictors of survival in Japanese patients with follicular lymphoma. Our predictive model may provide a basis for future therapeutic trials against follicular lymphoma in Japan.

Restricted V beta gene usage of tumour-infiltrating T lymphocytes in primary gastric malignant B-cell lymphoma.

Ten cases of primary gastric malignant lymphoma (PGL) were investigated by immunohistochemical and molecular genetic analysis. These cases were diagnosed histopathologically as follicular small cleaved cell type (1 case), diffuse small cleaved cell type (3 cases) and diffuse large cell type (6 cases) based on the WF (Working Formulation) classification. Seven cases classified as small cleaved or diffuse large cell type belong to low (4 cases) or high (3 cases) grade MALT lymphoma according to Isaacson's classification. All PGL belonged to B lineage cells according to immunohistochemical study and immunoglobulin rearrangements. Rearrangements of TCR beta chain genes were observed in four of the ten cases. The possibility that the TCR beta rearrangements were caused by tumour-infiltrating T-cells (TILs) was supported by the following observations: the tumours did not show T- and B-cell biphenotype, TCR beta exhibited functional VDJ rearrangement and V beta usage pattern was not a neoplastic type. Analysis of the repertoire of the TCR beta chain in TILs revealed a common usage of V beta 2 in the above four cases, and furthermore, predominant usage of a particular beta chain composed of V beta 2-D beta 2.1-J beta 2.3 was observed in one of the four cases. These results indicate that the TILs of PGL have a restricted TCR repertoire.

Alfacalcidol is a nontoxic, effective treatment of follicular small-cleaved cell lymphoma

Thirty-four patients with progressive low grade non-Hodgkin's lymphoma were treated with 1 microgram oral alfacalcidol daily. Complete response was seen in four patients and a partial response in four patients with an overall response rate of 24%. Median duration of response was 14 months. Disease stabilised in ten other patients (29%) and 16 patients (47%) had tumour progression. In the sub-group of patients with follicular, small-cleaved cell-lymphoma the overall response to treatment was 29%. Apart from one patient who had a mild transitory elevation of serum calcium there was no recorded toxicity from alfacidol. These results indicate that alfacalcidol has significant antitumour activity in patients with low grade non-Hodgkin's lymphoma of the follicular, small-cleaved cell type.

Acute lymphoblastic leukemia. An unusual case of primary relapse in the uterine cervix

Female genital tract involvement by hematologic neoplasms is uncommon and is usually associated with disseminated disease. Lymphoid neoplasms, which involve the cervix and uterus primarily, are usually of either diffuse large cell or small cleaved cell type, and rarely Burkitt's (small non-cleaved) lymphoma or granulocytic sarcoma. In this report the authors describe young woman with acute stem cell leukemia which was terminal deoxyribonucleotidyl transferase positive, and involved the bone marrow and peripheral blood. After induction of remission and a 2-year disease-free interval, she relapsed with involvement localized to the uterus and cervix. At relapse the leukemic cells expressed CD1, CD2, CD5, CD7, and CD4 or CD8, antigens of the common thymocyte compartment. The authors postulate that the T-cell antigens, known extracellular matrix receptors, may have determined the tissue infiltration: an unusual pattern of relapse.

Non‐Hodgkin's lymphoma of the major salivary gland: a morphologic and immunohistochemical study of 15 cases

A total of 15 cases of Japanese salivary gland lymphoma was analysed by conventional histology and also by immunoperoxidase staining of paraffin sections. The initial sites included: parotid gland (14 cases, 93%) and submandibular gland (1 case, 7%). The mean age was 59 yr, with a male to female ratio of 2.8:1. The only one patient (Case 9) with clinical evidence of Sjögren's syndrome showed the development of intrasalivary malignant lymphoma. Each lymphoma was classified according to the Working Formulation for Clinical Usage. The Working Formulation grades were 20% low, 67% intermediate, and 13% high. These neoplasms fell into six categories: follicular, small cleaved type (1 case); follicular, mixed small cleaved and large cell type (2 cases); follicular, large cell type (2 cases); diffuse, mixed small and large cell type (1 case); diffuse, large cell type (7 cases); and large cell, immunoblastic type (2 cases). Fifteen tumors were studied using a indirect immunoperoxidase method. A selected antibody panel was used, including B-cell markers (immunoglobulins, Ki-B3, L26), T-cell markers (UCHL-1 and MT1) and histiocytic markers (lysozyme, alpha 1-antitrypsin and cathepsin D). Eleven cases reacted with pan-B-marker (Ki-B3 and L26) and eight of them showed the presence of monoclonal cytoplasmic immunoglobulin (C-Ig). Following rigid criteria, monoclonal C-Ig of M kappa was demonstrated in one case of follicular, small cleaved cell type, one follicular, large cell type and two diffuse, large cell type; M lambda was demonstrated in one diffuse, large cell type; and G lambda was demonstrated in one follicular, mixed small cleaved and large cell type, and two diffuse, large cell type.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinicopathologic spectrum of cutaneous manifestations in systemic follicular lymphoma. A study of 11 patients.

Follicular lymphoma is rarely diagnosed on the basis of only a cutaneous biopsy. Eleven patients with primary follicular lymphoma of lymph nodes who developed skin lesions were studied. Skin lesions involved the scalp, head and neck, trunk, and buttocks and were small cleaved cell type in four cases, large cell type in three cases, and mixed type in four cases. The follicular pattern with a bottom-heavy distribution was identified in only six of the 11 cases. One case showed a nodular, perivascular pattern in the deep dermis and subcutaneous tissue. Four cases were characterized by a diffuse pattern of lymphocytic infiltrate. One patient with a diffuse pattern had an isolated subepidermal band of lymphoma cells representing primary cutaneous T-cell lymphoma. Cutaneous involvement by lymphoma previously diagnosed as low-grade (follicular growth pattern) transformed to higher grade disease in five of ten asynchronous cases. The 5-year survival rate was 60% among the transformed cases and 100% among the nontransformed cases. Extranodal cutaneous involvement in follicular lymphoma occurred in 3.8% of cases. The correct histologic diagnosis in a skin biopsy specimen can be established in cases with a follicular pattern (60%) with conventional histologic criteria such as redundancy of follicles, uniformity of follicular center cell composition, lack of interspersed phagocytic histiocytes, and absence of immunosecretory cellular elements such as plasma cells and immunoblasts.

Flow cytometric analysis of DNA ploidy in lymphomas of the thyroid.

Four cases of primary non-Hodgkin's lymphoma (NHL) of the thyroid were studied using flow cytometric (FCM) DNA analysis of propidium iodide-stained nuclei retrieved from formalin-fixed, paraffin-embedded tissue. Two of the four cases were aneuploid and two were euploid. In the two euploid cases, both patients are alive and without evidence of recurrent disease after an average of 4 years follow-up. Of the two aneuploid cases, one patient is alive and free of recurrent disease after 1 year. In the other aneuploid case, the patient died of disseminated disease 8 months after presentation despite having a low-grade (follicular, predominantly small cleaved cell type) and low-stage (tumor confined to thyroid at presentation) lymphoma. These data suggest that the DNA ploidy of primary NHL of the thyroid can be determined using fixed, paraffin-embedded tissue. Our results also suggest that a large study to assess the prognostic value of this technique is warranted.

A method combining morphological, immunocytochemical and chromosomal examinations of the same cell in the study of lymphoproliferative diseases.

6 cases of different lymphoproliferative diseases were studied with the new MAC (Morphology-Antibody-Chromosome) method in order to find out 1) if the abnormal karyotype is confined to the monoclonal cell population, 2) if there are, within this clone, also cells with a normal karyotype, and 3) if the method can help the pathologist to diagnose malignant lymphoproliferative diseases. The MAC method allows a simultaneous study in the same metaphase cell of the karyotype, surface markers, and some morphological features. In all cases in which a monoclonal cell proliferation was detected immunohistologically, the MAC examination showed a chromosomal abnormality for the same light chain as was detected in immunohistology, but not in other cells. In all but a single case, all mitotic cells belonging to the clonal cell proliferation had an abnormal karyotype. In this case with lambda clonality, 2/8 lambda-positive mitoses had a normal karyotype. However, all the normal mitoses occurred in small lymphocytes whereas the abnormal mitoses were seen in large blastic cells. In 1 case, the MAC method helped in confirming the diagnosis of malignant lymphoma (nodular small cleaved cell type). Especially in lymphomas composed of a mixed cell population, the MAC method makes it possible to find out which cell types have an abnormal karyotype and which have a normal karyotype.

Stage III follicular lymphoma: durable remissions with a combined chemotherapy-radiotherapy regimen.

From 1975 to 1982, 74 patients with stage III follicular lymphoma were treated with a combined modality protocol which included chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo), and radiotherapy to involved regions. This program resulted in a complete remission (CR) rate of 81%, a 5-year survival of 75%, and 5-year relapse-free survival (RFS) of 52% for all patients. Analysis of potential factors affecting treatment outcome revealed a significantly better CR rate for patients with small cleaved cell type (97%) than for patients with mixed (73%) or large-cell (57%) histologies. The 5-year survival was significantly better for patients with small cleaved (91%) and mixed (84%) cell types than for large cell (40%). In addition, bulky abdominal disease and elevated serum lactate dehydrogenase (LDH) were significant adverse prognostic factors for CR and for survival. Toxicity was moderate. No secondary leukemias have occurred. This combined modality regimen resulted in prolonged remission and potential cure for over half of patients who achieved CR, and is particularly encouraging for those with follicular small cleaved and mixed histologies.

Evaluation of malignant lymphomas using three classifications and the working formulation: 482 cases with median follow-up of 11.9 years

Three classifications and the Working Formulation for non-Hodgkin's lymphomas have been studied in 482 patients with a median follow-up of 11.9 years. Each classification was evaluated independently, and their similar and discrepant aspects were analyzed by comparing subgroups in the different schemes. Clinical staging was essential in the evaluation of some categories. There are several differences between the classifications that are not readily reconcilable. The Rappaport classification's principal groups are heterogeneous. Separation of follicular lymphomas into small and large cleaved cell types (Lukes-Collins) is significant. The addition of a follicular mixed cell type (Rappaport, Working Formulation) detracts from this significance. Centrocytic and lymphoplasmacytic tumors (Kiel) are well-defined categories and important in understanding some deficiencies in the other classifications. The small cleaved cell type, diffuse (Lukes-Collins, Working Formulation) is heterogeneous. Diffuse lymphomas of mixed cell types are poorly defined subgroups. Excluding lymphoblastic types, the presence of plasmacytic differentiation is important in identifying the high-grade lymphomas with the poorest prognosis. These results suggest that adjustments should be made in the classifications and in the Working Formulation.

Mantle-zone lymphoma

We analyzed the distribution and immunologic phenotype of the neoplastic cells in eight cases of mantle-zone lymphoma. Although in all the cases the follicle centers appeared reactive on routine histologic examination, polyclonal staining for immunoglobulin was found in the follicle centers in only five of the eight cases; in the other three cases the follicle centers were monoclonal. In three cases, the immunologic phenotype was that of centrocytic (diffuse small cleaved cell) lymphoma: IgM+IgD+B1+B2+Ia+Tl+. In one case the phenotype was that of a follicular (centroblastic/centrocytic) lymphoma: IgG+B1+B2+Ia+CALLA+. In the other four cases, the phenotype was IgM+B1+B2+ or B2-Ia+; this phenotype can be seen in diverse B cell lymphomas. The phenotype of normal mantle-zone cells (IgM+IgD+B1+B2+Ia+) was not reproduced by any of the lymphomas. A mantle-zone pattern may be produced by either follicular or diffuse lymphomas of predominantly small cleaved cell type, and does not indicate an origin from the cells of the normal mantle zone.

The clinicopathologic spectrum of lymphomatoid papulosis: Study of 31 cases

Herein we review the Mayo Clinic experience with thirty-one cases of lymphomatoid papulosis seen since 1965. All patients had chronic, recurrent, and self-healing erythematous papulonodular lesions, which often became pustular, ulcerated, and resolved with scarring. The clinical features often corresponded to those seen in Mucha-Habermann disease; however, the predominant histopathologic feature was an infiltrate composed primarily of atypical lymphoid cells suggestive of malignant lymphoma. In six patients, a lymphoproliferative disorder was eventually diagnosed. There were two cases of mycosis fungoides (stage I), one case of nodular sclerosing Hodgkin's disease, and three cases of malignant lymphoma--one diffuse mixed large and small cell type with features of T-immunoblastic type, one diffuse large cell type, and one follicular small cleaved cell type. The clinical course of the lymphomatoid papulosis was unaffected by chemotherapy for the lymphoproliferative disorder. Our data indicate that, with sufficient duration of follow-up, malignant lymphoma may develop in some patients with lymphomatoid papulosis.

Non-hodgkin's lymphomas.A clinicopathologic study comparing two classifications

The Lukes and Collins classification is based on the premise that malignant lymphomas (ML) should be classified on the basis of immunologic markers and that the B, T or „undefined”︁ nature of these tumors can be morphologically recognized. The difficulties of achieving this are discussed in this study. The „undefined”︁ type of these investigators posed a particular problem since it appears to be a heterogeneous group which includes ML currently classified as „histiocytic,”︁ lymphoblastic and undifferentiated. The prognosis appeared to be closely related to cytologic types in both the Rappaport and the Lukes and Collins classifications. In the follicular center cell (FCC) lymphomas the overall median survival of patients with follicular lymphomas was longer than that of patients with diffuse lymphoma (p < 0.0001). Extending this comparison to cell types we found longer median survivals of follicular lymphomas in each subgroup but with variable statistical significance. For all cleaved cell lymphoma the p value was 0.02, for the small cleaved cell type 0.16, for the large cleaved cell type 0.09 and for the large noncleaved cell type 0.1. The lymphomas which we identified as being of the diffuse large cleaved FCC type seemed to have a relatively favorable prognosis in comparison to other diffuse large cell lymphomas (p ρ 0.08). However, within this latter group a morphologic separation into large noncleaved FCC, immunoblastic, and true histiocytic seemed difficult. For the purpose of this study, however, we attempted to apply the designation of immunoblastic sarcoma to tumors composed of large lymphoid cells with plasmacytoid features, but found no differences in survival when comparing it with diffuse large noncleaved FCC tumors.