Showing papers on "Large cell published in 1995"

Activation of the precursor of gelatinase A/72 kda type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis

Abstract: We have identified a novel membrane-type matrix metalloproteinase (MT-MMP) expressed on the cell surface and inducing activation of pro-gelatinase A in vitro. In this study, we further examined the possibility that MT-MMP is the activator of pro-gelatinase A in tumors as well as in vitro. Expression of MT-MMP mRNA was analyzed by Northern blotting in 58 cases of human lung carcinomas. MT-MMP mRNA expression was increased in tumor tissues compared with adjacent normal tissues. The ratio of MT-MMP mRNA levels in tumor/normal tissues (T/N ratio) was 3.19 ± 1.62 in 29 cases of adenocarcinoma, 3.09 ± 1.44 in 24 cases of squamous cell carcinoma, 4.40 ± 0.47 in 3 cases of large cell carcinoma and 3.63 ± 2.11 in 2 cases of small cell carcinoma, respectively. Activated gelatinase A, as detected by gelatin zymography, was also predominant in tumors compared with normal tissue counterparts, though the difference in mRNA levels was not significant. The activation ratio of gelatinase A in tumor vs. normal tissues correlated well with that of MT-MMP mRNA expression and with lymph node metastases. Our findings suggest that MT-MMP is indeed the tumor-specific activator of pro-gelatinase A in lung carcinomas and is important to initiate invasion of basement membranes. © 1995 Wiley-Liss, Inc.

Enhanced Apoptosis Predicts Shortened Survival in Non-Small Cell Lung Carcinoma'

Abstract: This study was undertaken to determine the extent of apoptosis in lung carcinoma and to evaluate it as a prognostic marker. A series of 75 lung carcinomas (47 squamous cell carcinomas, 24 adenocarcinomas, 3 small cell carcinomas, and 1 large cell carcinoma) was analyzed for the extent of apoptosis by using the 3' end-labeling method of DNA in tissue sections. Apoptosis was correlated with the rate of cell proliferation, the immunohistochemically detectable p53 and bcl-2, the extent of tumor necrosis, and the survival data. The end-labeling method allowed a precise evaluation of the extent of apoptosis. In tumor tissue, the number of apoptotic bodies was roughly 2-fold greater than the number of apoptotic cells, whereas in nonneoplastic control tissues, the ratio was 1:1. The apoptotic indexes (percentages of apoptotic cells and bodies among tumor cells) were slightly higher in adenocarcinoma than in squamous cell carcinoma. There was no association between the extent of apoptosis and the expression of proliferating cell nuclear antigen or p53. On the other hand, tumor necrosis correlated significantly with proliferating cell nuclear antigen and p53 positivity (P = 0.00025 and 0.00087, respectively). Surprisingly, the extent of apoptosis was also found to be independent of the expression of bcl-2. Patients with apoptotic indexes greater than 1.5% had significantly shorter survival time than patients with apoptotic indexes equal to 1.50% or less (P < 0.01 by log rank). Aberrant p53 positivity also predicted a poor prognosis (P < 0.002 by log rank). By multivariate analysis, enhanced apoptosis showed a 1.9-fold risk (P = 0.04), and p53 positivity showed a 2.3-fold risk (P = 0.005) for a shortened survival. We conclude that both enhanced apoptosis and p53 positivity are independent prognostic markers in non-small cell lung carcinoma, predicting shortened survival time of the patients.

Neutrophil-rich, Ki-1-positive anaplastic large-cell malignant lymphoma.

Abstract: The presence of neutrophils, in the absence of necrosis, is uncommon in malignant lymphoma (ML). We identified a subgroup of Ki-1-positive anaplastic large cell ML (Ki-1 ALCL) in which neutrophils were a prominent component. Six of 20 cases of Ki-1 ALCL had a significant neutrophil infiltrate that varied from 5 to 10% to > 50% of cells per high power field. Neutrophils were not seen in 100 cases of other types of ML reviewed. Patients were first seen with skin lesions (four), localized lymphadenopathy (three), generalized lymphadenopathy (one), and localized extranodal disease (one). All had primary disease. Two patients had peripheral neutrophilia. Three of six patients had clinical stage IV disease. Four patients are currently in clinical remission; one died of recurrent disease; and one patient with acquired immunodeficiency syndrome (AIDS) died of Pneumocystis carinii pneumonia. Four cases demonstrated a T-cell phenotype, one of which arose in a patient with AIDS. Two had a B-cell phenotype. All cases were positive for CD30 (Ki-1). These observations expand the morphologic spectrum of Ki-1 ALCL to include a neutrophil-rich variant. We conclude that the presence of neutrophils is another morphologic feature shared by some cases of Ki-1 ALCL, lymphomatoid papulosis, and Hodgkin's disease, which suggests a possible pathogenetic link among them.

Lymphoma of the kidney. A report of 11 cases

Abstract: We describe 11 patients first seen with symptoms or signs related to lymphoma predominantly or exclusively involving one or both kidneys. The patients were seven men and four women, aged 40-77 years (median, 67). Seven of them had one or more other prior (four), subsequent (two) or both simultaneous and subsequent (one) primary malignant or premalignant lesions. The presenting symptoms of the patients with lymphoma included local pain (five cases), loss of appetite or nausea (four cases), hematuria (two cases), weight loss (two cases) or malaise (two cases). One patient had renal failure at presentation. One lymphoma was an incidental finding at the time of aneurysm resection. Nine patients had unilateral disease; two patients had bilateral disease. Six unilateral cases were initially considered on clinical (five) or clinical and pathological (one) evaluation to be primary carcinomas of the kidney. Gross examination of nephrectomy specimens revealed fleshy or firm, yellow, tan, or gray tumors from 5.7 to 22 cm (median, 7.5) in greatest dimensions that frequently invaded perinephric fat and adjacent structures. The lymphomas were subclassified as diffuse large cell (seven cases), follicular and diffuse large cell (one case), small lymphocytic plasmacytoid (two cases), and small noncleaved cell lymphoma (non-Burkitt's type) (one case). Immunophenotyping in nine cases revealed that all were B-lineage tumors. Three patients had Ann Arbor stage I disease, three had stage II, and five had stage IV. On follow-up, ranging from 1 week to 169 months (median, 15 months), 5 patients were alive and free of lymphoma. Four patients died of progressive disease 1 week to 23 months after diagnosis. One patient is alive at 4 months but has not completed chemotherapy. One asymptomatic patient has not been treated. Renal lymphomas are predominantly large-cell lymphomas of B-lineage affecting middle-aged and older adults and often can be treated successfully. Both clinically and pathologically, they can be mistaken for carcinomas of the kidney. A high proportion of patients in this series had malignant tumors of other types.

Bone Marrow Involvement in Anaplastic Large Cell Lymphoma: Immunohistochemical Detection of Minimal Disease and Its Prognostic Significance

Abstract: Bone marrow involvement by anaplastic large cell anaplastic large cell (ALC) lymphoma can be difficult to detect on routine morphologic examination alone. In a series of 42 patients with ALC lymphoma, the authors analyzed: (1) the usefulness of a limited panel of monoclonal antibodies directed against CD30 (Ber-H2, HRS4) and epithelial marrow involvement on routinely processed biopsy specimens; and (2) the prognostic significance of bone marrow involvement as detected on both morphologic and immunohistochemical grounds. On conventional examination, 17% of the patients were found to have bone marrow involvement at diagnosis. However, after immunohistochemical analysis, occult malignant cells were detected in 23% of the patients with negative bone marrow biopsy on routine histology. The low percentage of positive cases on routine morphologic examination compared to immunohistochemical examination was related to: (1) the scarcity of neoplastic cells which were scattered among hematopoietic cells; (2) the difficulty of distinguishing malignant cells from immature hematopoietic elements; and (3) the absence of alteration of the reticulin network. The authors observed a significant association between marrow infiltration and the presence of hematologic abnormalities (mostly anemia or cytopenias) at diagnosis, both in children and adult patients. More importantly, a significant lower survival was seen in patients with bone marrow involvement compared to those without bone marrow involvement. Immunohistochemistry with anti-CD30 and anti-EMA antibodies should be performed systematically in bone marrow biopsies from patients with ALC lymphoma to reliably identify the presence of bone marrow involvement that appears to carry a poor prognosis.

Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron microscopic study

Abstract: The cellular nature of the giant eosinophilic cells of tuber and of the cells comprising subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) remains unclear. To assess the characteristics of these lesions, 13 tubers and 6 SEGA were immunohistochemically studied with glial and neuron-associated antigens. In addition to conventional ultrastructure, 6 tubers and 8 SEGA were fibrillary acidic protein (GFAP) and somatostatin. Eosinophilic giant cells of tubers were positive for vimentin (100%), GFAP (77%) and S-100 protein (92%); such cells were also found to a various extent to be reactive for neuron-associated antigens, including neurofilament (NF) proteins (38%) or class III β-tubulin (77%). SEGA also showed variable immunoreactivity for GFAP (50%) or for S-100 protein (100%); NF epitopes, class III β-tubulin, and calbindin 28-kD were expressed in 2 (33%), 5 (83%) and 4 (67%) cases, respectively. Cytoplasmic staining for somatostatin (50%), met-enkephalin (50%), 6-hydroxytryptamine (33%), β-endorphin (33%) and neuropeptide Y (17%) was noted in SEGA, but not in tubers. Ultrastructurally, the giant cells of tubers and the cells of SEGA contained numerous intermediate filaments, frequent lysosomes and occasional rectangular or rhomboid membrane-bound crystalloids exhibiting lamellar periodicity and structural transition to lysosomes. Some SEGA cells showed features suggestive of neuronal differentiation, including stacks of rough endoplasmic reticulum, occasional microtubules and a few dense-core granules. Furthermore, in one case of tuber, a process of a single large cell was seen to be engaged in synapse formation. Intermediate filaments within a few cells of both lesions were decorated by gold particle-labeled GFAP antiserum. Within the tumor cells of SEGA, irregular, non-membrane-bound, electron-lucent areas often contained somatostatin-immunoreactive particles, whereas the latter could not be detected in tuber. The present study provides further evidence of divergent glioneuronal differentiation, both in the giant cells of tubers and the cells of SEGA. The findings of similar cells at different sites, including the subependymal zone, white matter (“heterotopias”), and cortex indirectly supports the idea that these lesions of TS result from a migration abnormality.

Expression of the multidrug resistance-associated protein ( MRP ) gene in non-small-cell lung cancer

Abstract: We examined the levels of expression of the multidrug resistance-associated protein (MRP) gene quantified by Northern blot analysis in comparison with those of the MDR1 gene determined by reverse transcription-polymerase chain reaction (RT-PCR) in 104 non-small-cell lung cancer (NSCLC) specimens [59 adenocarcinoma (Ad), 40 squamous cell carcinoma (Sq), four large cell carcinoma (La) and one adeno-squamous carcinoma (AdSq)]. Thirty-three (31.7%) of the 104 NSCLC expressed the MRP gene at various levels. The NSCLC showing high (++) levels of MRP gene expression (19 out of 33, 57.6%) were predominantly squamous cell carcinomas (Ad, 5; Sq, 13; La, 1) (P < 0.05). Six of the eight NSCLCs expressing high levels of MRP mRNA and no MDR1 (MRP ++, MDR1-) were squamous cell carcinomas. Sixty-one of the 104 NSCLC patients received chemotherapy with MRP-related anti-cancer drugs [vindesine (VDS) and etoposide (VP-16)]. Twenty-three patients (37.7%) with tumour expressing high or moderate levels of MRP showed significantly worse prognoses than those with non- or low-MRP-expressing tumours (P < 0.05). These results suggest that the level of MRP gene expression is related to the histopathology and prognosis of NSCLC.

Primary renal non-Hodgkin's lymphoma. An unusual extranodal site

Abstract: Background. Primary renal non-Hodgkin's lymphoma (NHL) is rare. Because the renal parenchyma does not have lymphatics, the existence of this entity has been questioned. The goal of this study was to determine the clinical presentation, pathologic features, and disease course of patients with primary renal NHL and review the pertinent literature on this unusual extranodal NHL. Methods. All medical records from the Mayo Clinic from 1976 to 1992 with the diagnosis of renal NHL were retrospectively reviewed. One-hundred seventy-six cases were identified, five of which met the criteria for primary renal NHL. The clinical, pathologic, and radiographic features were reviewed in detail and are the basis of this report. Results. The median age at diagnosis of the five patients with primary renal NHL was 60 years (range, 52-63 years) with a male-to-female ratio of 2 :3. All patients had flank pain as their initial presentation. Urinalysis was abnormal in only one patient. In three patients, the serum creatinine was elevated. Tumor histology was diffuse large cell in four cases ; and small noncleaved non-Burkitt's in one. All five were B-cell immunophenotype. All patients received combination chemotherapy. Although the median survival for the group was only eight months, two remain in complete remission longer than 80 months from therapy. These two had total removal of macroscopic lymphoma and received combination chemotherapy and consolidation radiotherapy. Conclusions. Primary renal non-Hodgkin's lymphoma does exist. Patients whose lymphomas were completely resected macroscopically and who received combination chemotherapy with consolidation radiation therapy had long disease free survival. Patients with bilateral renal involvement or no debulking of the renal lymphoma tended to have poorer survival. Cancer 1995 ;75 :2258-61.

Expression of c-ets-1, collagenase 1, and urokinase-type plasminogen activator genes in lung carcinomas.

Abstract: The c-ets-1 transcription factor has been involved in the in vitro transactivation of matrix-degrading protease genes that might play an important role in tumor invasion. Using in situ hybridization, we analyzed serial frozen sections for c-ets-1, collagenase 1, and urokinase-type plasminogen activator gene expression in 54 lung carcinomas including 34 non-neuroendocrine carcinomas (18 squamous carcinomas, 10 adenocarcinomas, 3 large cell carcinomas, and 3 basaloids) and 20 neuroendocrine carcinomas (7 small cell lung carcinomas, 4 large cell neuroendocrine carcinomas, 4 well differentiated neuroendocrine carcinomas, and 5 carcinoids). c-ets-1 gene was expressed in stromal cells in 44/54 lung carcinomas including one metastasizing carcinoid. c-ets-1 transcripts were also detected in cancer cells more frequently in neuroendocrine than in non-neuroendocrine carcinomas (P = 0.0059) and in stages III and IV and metastasis more frequently than in stages I and II ( P = 0.0065). Collagenase 1 gene was expressed in 16/34 non-neuroendocrine tumors and in 1/20 neuroendocrine tumors, either in stromal (12/17) or in cancer cells (6/17). Urokinase-type plasminogen activator mRNAs were expressed in 45/54 lung carcinomas in stromal and/or cancer cells. In non-neuroendocrine tumors, c-ets-1 and collagenase 1 gene expressions in stromal cells were correlated. These results demonstrate that the transcription factor c-ets-1, collagenase 1, and urokinase-type plasminogen activator are involved in lung cancer invasion and suggest that c-ets-1 protein might transactivate collagenase 1 gene during tumor invasion.

A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells

Abstract: The BCL-6 gene is frequently involved in translocations occurring at the 3q27 locus and is rearranged in approximately 30% of diffuse large cell lymphomas and in a small fraction of follicular lymphomas. The BCL-6 gene encodes for a Kruppel-type zinc-finger protein, the cell/tissue expression and function of which is unknown. In this study, we describe a new monoclonal antibody (PG-B6) that is specifically directed against a fixative-sensitive epitope on the amino-terminal region of the BCL-6 protein. By immunocytochemical analysis, BCL-6 localizes in the nucleus where PG-B6 staining gives a microgranular/diffuse pattern with exclusion of the nucleoli. The main reactivity of PG-B6 in tonsil and spleen is with the nuclei of germinal center B cells, whereas B cells within the mantle and marginal zones do not express BCL-6. No other lymphoid cells in the tonsil express BCL-6 except for a subset of CD3+/CD4+ intrafollicular and interfollicular T cells. A few lymphoid cells of unknown phenotype express BCL-6 in the thymus. Extra-lymphoid BCL-6 expression includes a weak nuclear positivity of epithelia. In non-Hodgkin's lymphomas, BCL-6 expression parallels that observed in normal lymphoid compartments, eg, expression in germinal center-derived tumors (follicular and diffuse large cell lymphomas), but not in mantle cell and marginal zone lymphomas. In most diffuse large cell lymphomas, the BCL-6 protein is expressed at high levels in cases with or without BCL-6 gene rearrangements. These findings indicate that BCL-6 expression is specifically regulated during B lymphocyte development and suggest that BCL-6 may play a role during B cell differentiation in the germinal center.

Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents.

Abstract: The multifocal origin of prostate cancer suggests a pan-organ defect in a tumor suppressor pathway. Although structural mutations in the p53 gene have been implicated in late-stage prostate cancer, little is known about the p53 response to genotoxic stress in normal human prostatic epithelial cells from which adenocarcinomas originate. We found that the majority (10 of 12) of epithelial cell cultures derived from histologically normal tissues of radical prostatectomy specimens failed to exhibit p53 accumulation in response to ionizing radiation. Epithelial cell cultures derived from benign prostatic hyperplasia and a primary prostatic adenocarcinoma also failed to accumulate p53 in response to ionizing radiation. In contrast, cultures of prostatic stromal cells derived from normal, benign prostatic hyperplasia, or adenocarcinoma tissues exhibited a 3-9-fold induction of p53 within 1-3 h after irradiation. Since p53 regulates a cell cycle checkpoint through the induction of the cyclin-cdk inhibitor p21, we examined p21 accumulation and cell cycle arrest following exposure to ionizing radiation. With one exception, epithelial cells that did not display increased p53 or p21 induction did not demonstrate a significant G1-S arrest in response to ionizing radiation, whereas stromal cells that accumulated p53 and p21 exhibited a large cell cycle arrest. These results indicate a functional difference between the DNA damage response of epithelial and stromal prostatic cells and suggest a possible mechanism for the increased susceptibility of prostatic epithelial cells to accumulate genetic alterations.

The neu-protein and breast cancer.

Abstract: The neu-protein is overexpressed in about 20% of invasive duct cell carcinomas of the breast. The only reliable sign for neu-overexpression by immunohistochemistry is membrane staining. Its overexpression is correlated with decreased overall survival and disease free survival due to increased metastatic activity of neu-overexpressing tumour cells. This increased metastatic potential is a consequence of the motility enhancing activity of the neu-protein, which is exclusively expressed on pseudopodia, and to a lesser extent of its growth stimulating effect. From a clinical point of view, the assessment of neu-overexpression in breast cancer might become a useful tool in the future treatment of patients by chemotherapy, since patients whose tumour shows neu-overexpression benefit from higher doses of chemotherapy. The molecule plays a key role in the pathogenesis of Paget's disease of the breast. A chemotactic factor which is secreted by epidermal keratinocytes attracts the Paget cells to spread into the epidermis and acts via the neu-protein. In ductal carcinoma in situ, the combination of neu-overexpression and large cell type is highly correlated with extent of disease and therefore neu-overexpression might be a predictive marker for recurrence of disease after tumour resection.

KP1/CD68 expression in malignant neoplasms including lymphomas, sarcomas, and carcinomas.

Abstract: Expression of KP1/CD68 macrophage-associated antigen in a series of 840 selected malignant neoplasms, including immunomorphologically characterized cases of non-Hodgkin's lymphoma (NHL) (434), Hodgkin's disease (HD) (115), soft tissue sarcoma (147), carcinoma (49), and other tumors (95), was examined. KP1 expression was detected in a significant number of NHLs (107 of 434; 24.7%), most of them (65 of 107; 60.7%) of the diffuse small cell subtype. Only 14 of the 155 large cell lymphomas, compared to 10 of the 51 Ki-1/CD30+ anaplastic large cell (ALC) lymphomas examined, were KP1 positive. Conversely, none of the T-lineage NHL--other than Ki-1/CD30+ ALC lymphomas--or the HD cases tested was labeled by KP1 antibody. Among the other neoplasms tested, KP1 was reactive with a variable proportion of cases of malignant fibrous histiocytoma (19 of 24; 79.2%), malignant schwannoma (8 of 22; 36.4%), liposarcoma (3 of 9; 33.3%), leiomyosarcoma (8 of 37; 21.6%), cutaneous or metastatic melanoma (51 of 73; 69.9%), and renal cell carcinoma (3 of 5; 60%). These results indicate that KP1 shows a relatively wide spectrum of immunoreactivity with malignant neoplasms of presumed non-histiocyte origin, thus arguing against its expected specificity and high value in diagnostic pathology. Although the significance of KP1 expression by some subsets of NHLs remains to be elucidated, its close association with B-cell NHLs, mostly of the diffuse small cell type, should stimulate further pathologic and clinical investigations.

Fine needle aspiration cytology of primary and metastatic lesions of the adrenal gland. A series of 188 biopsies with radiologic correlation.

Abstract: OBJECTIVE : To determine the efficacy of fine needle aspiration (FNA) in the diagnosis of primary and metastatic lesions of the adrenal gland in conjunction with the radiologic size of the lesion. STUDY DESIGN : One hundred eighty-eight FNA biopsies performed between 1988 and 1992 with a diagnostic rate of 86% (161 cases) were reviewed and correlated with the radiologically (computed tomography, ultrasound) measured size of the lesion and follow-up. RESULTS : Eighty-one cases (43%) were primary adrenal lesions, and 80 (43%) were metastatic tumors. Three large cell lymphomas and two adrenal histoplasmoses were also noted. The most common primary site of metastatic tumors was the lung ; these 55 cases (29%) included 47 adenocarcinomas and 3 small cell, 2 large cell and 3 squamous cell carcinomas. The other metastatic tumors were 5 melanomas, 7 renal cell carcinomas and 1 mixed mullerian tumor. The size of the metastatic tumors averaged 5.1 ± 2.5 cm (± SD) and ranged from 1.5 to 10 cm in greatest diameter. Benign cortical nodules (61 cases, 32%) were the most common primary adrenal lesion, followed, in decreasing frequency, by 11 cortical neoplasms/carcinomas, 5 pheochromocytomas and 1 myelolipoma. The benign cortical nodules/adenomas measured an average of 2.4 ± 0.8 cm in greatest diameter and ranged from 1 to 4 cm. The cortical neoplasm/carcinoma sizes ranged from 4 to 12 cm. CONCLUSION : These data suggest that FNA in conjunction with the radiologically measured size of adrenal lesions is a specific and sensitive method of evaluating primary and metastatic lesions of the adrenal gland. It is also an important diagnostic tool in cancer staging, obviating open surgical procedures for many patients. (Acta Cytol 1995 ;39 :843-851)

The value of PE-10, a monoclonal antibody against pulmonary surfactant, in distinguishing primary and metastatic lung tumours.

Abstract: A new monoclonal antibody (PE-10) raised against components of pulmonary surfactant has been assessed for its ability to distinguish primary from secondary carcinomas in the lung. We applied this antibody to a series of 107 primary lung carcinomas, 40 adenocarcinomas of other sites, and 26 cases of adenocarcinoma metastatic to lung and pleura. Of the primary lung carcinomas, all the non-mucinous bronchiolo-alveolar carcinomas were positive whereas all the mucinous cases were negative; 60% of other types of adenocarcinoma were positive and 10% of large cell undifferentiated carcinomas, 20% of small cell carcinomas and 40% of atypical carcinoids also showed focal positivity. Squamous cell carcinomas were all negative. Adenocarcinomas of the breast, kidney, large bowel and ovaries were all negative, as were all 26 cases of adenocarcinoma metastatic to the lung and pleura. We conclude that this antibody is highly specific and moderately sensitive for primary tumours of the lung.

B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter's syndrome.

Abstract: A 70-year-old woman with a 2-year history of B-cell chronic lymphocytic leukemia (CLL) developed headache, fever, chills, and weakness. Bone marrow examination revealed both CLL and large cell immunoblastic lymphoma (Richter's syndrome). As expected, the CLL was of B-cell lineage. The neoplasm expressed low-density monotypic IgM lambda, the pan-B-cell antigens CD19, CD20, and CDw75, and the CD5 and CD43 antigens. The large cell immunoblastic lymphoma was of T-cell lineage, positive for the CD45RB, CD3, CD45RO, and CD43 antigens, and negative for the CD20 and CDw75 antigens. Both neoplastic components were negative for Epstein-Barr virus RNA and latent membrane protein. Although 3% to 5% of patients with B-cell CLL may develop higher-grade lymphoma, usually the lymphoma is of B-cell lineage and often represents a histologic manifestation of clonal evolution. Less commonly, B-CLL patients may develop transformation to a higher grade tumor that resembles Hodgkin's disease. Both the usual form of Richter's syndrome and particularly the Hodgkin's variant of Richter's syndrome may be associated with Epstein-Barr virus. Patients with B-cell CLL rarely develop a higher grade lymphoma of T-cell lineage. To our knowledge, only one other example has been reported in the literature. Epstein-Barr virus was not associated with either neoplasm in this case.

Transferrin receptor expression in nonsmall cell lung cancer. Histopathologic and clinical correlates

Abstract: Background In the search for tumor-related antigens with survival-predictive value, previous studies have yielded varied conclusions regarding the expression of one such antigen, the transferrin receptor in lung cancer The goal of this study was to define the frequency of expression of transferrin receptor in lung cancer specimens and gather preliminary data regarding the prognostic value of this tumor-related antigen Methods Tissue immunoreactivity was studied with a murine monoclonal antibody to transferrin receptor in patients with nonsmall cell lung cancer who underwent surgical resection at the Medical Center Hospital of Vermont during the period from January, 1988, to May, 1991 Results The study group consisted of 32 patients (21 males and 11 females) with an average follow-up length of 27 months (standard deviation of 16 months) There were 17 patients with adenocarcinoma, 14 with squamous cell carcinoma, and 1 with large cell carcinoma At the end of data accumulation, a total of 16 deaths had been recorded (8 with squamous cell, 8 with adenocarcinoma) Normal lung tissue did not stain for transferrin receptor ; however, 13 of 17 (76%) adenocarcinomas, 13 of 14 (93%) squamous cell carcinomas, and the 1 large cell carcinoma stained positively for transferrin receptor Staining for transferrin receptor was graded according to pattern and intensity and categorized as absent-weak or strong Survival analysis was performed to evaluate patient outcome based on a variety of clinical and experimentally determined characteristics Groups based on N-status (NO vs N1 + N2, P = 008), stage (Stage 1 vs Stage 2 + 3, P = 013), age (younger than 60 vs 60 years or older, P = 009), and transferrin receptor staining (absent-weak vs strong, P = 014) achieved nearly significant differences in survival Further analysis of the differences in survival for groupings based on transferrin receptor staining found that these differences in survival reached significance for patients with larger tumors (T2 or T3, P = 002) Conclusions Transferrin receptor is expressed in the majority of lung cancers and the presence of transferrin receptor in nonsmall cell lung cancers may be an indicator of poorer prognosis in certain groups of patients Cancer 1995 ; 76 :20-5

Bcl-2 oncoprotein is widespread in lymphoid tissue and lymphomas but its differential expression in benign versus malignant follicles and monocytoid B-cell proliferations is of diagnostic value.

Abstract: The distribution of Bcl-2 oncoprotein was studied immunohistochemically in formaldehyde-fixed and paraffin-embedded reactive and neoplastic lymphoid tissue. The potential of Bcl-2 for the differential diagnosis of follicular lesions was emphasized, and the results on follicular lesions were correlated with those of polymerase chain reaction (PCR) assay of the immunoglobulin heavy chain gene rearrangement. In hyperplastic lymphoid tissue, Bcl-2 reactivity was widespread, including germinal center surroundings, scattered cells within the germinal centers, and the T-cell areas in general. Distinctively negative lymphoid populations included the majority of germinal center cells, and the negative staining pattern was maintained in cases of florid hyperplasia. In contrast, follicular lymphoma cells were consistently Bcl-2 positive. The immunohistochemical Bcl-2 reactivity of lymphoma follicles correlated with the clonal PCR amplification pattern of the immunoglobulin heavy chain gene; all Bcl-2-negative hyperplasias revealed a non-clonal pattern. Clusters of monocytoid B cells were Bcl-2 negative, whereas monocytoid B-cell lymphomas and closely related MALT lymphomas were positive. All other small cell non-Hodgkin's lymphomas of B-cell types showed nearly uniform Bcl-2 reactivity, whereas large cell B-cell lymphomas were variably positive (74%). In Hodgkin's cells, Bcl-2 reactivity was seen in the neoplastic populations of most cases of nodular sclerosis and mixed cellularity types, whereas the L&H and Reed-Sternberg cells in lymphocyte predominance Hodgkin's disease were negative in most cases. Bcl-2 immunohistochemistry thus appears very valuable in the differential diagnosis of follicular hyperplasia and neoplasia, and it may help to distinguish between reactive and neoplastic monocytoid B cells. However, Bcl-2 immunohistochemistry is not useful in the subtyping of B-cell lymphomas.

Apocrine adenosis: a precursor of aggressive breast cancer?

Abstract: AIM--To investigate overexpression of c-erbB2, expression of the p53 protein product and proliferation rates in benign breast lesions with specific reference to apocrine adenosis. METHODS--Twenty one cases of apocrine adenosis were stained with monoclonal antibodies to p185, the protein product of the c-erbB2 oncogene, the protein product of the p53 tumour suppressor gene and to the cell cycle related protein Ki67. Three cases were associated with concomitant ductal carcinoma in situ of large cell type and two were associated with invasive tubular or cribriform carcinoma. RESULTS--Twelve (57.1%) cases showed membrane staining for c-erbB2 oncoprotein of apocrine cells within sclerosing adenosis and six (28.6%) had occasional p53 protein positive cells. One case not associated with carcinoma showed extensive staining of apocrine metaplasia outside the area of apocrine adenosis. The proliferation rate, as measured by Ki67 staining, was increased in some of the lesions and all lesions showed at least some of the cells to be in the cell cycle. CONCLUSIONS--The expression of abnormal oncogene products and increased proliferation in some of these apocrine lesions questions the supposed degenerative nature of the atypia seen in such cases and suggests that there may be an association between these lesions and large cell ductal carcinoma in situ and hence invasive carcinoma.

Cutaneous Presentations of Lymphoma in Human Immunodeficiency Virus Disease: Predominance of T-Cell Lineage

Abstract: Background and Design: Most non-Hodgkin's lymphomas in patients with human immunodeficiency virus infection are of B-cell lineage. Cutaneous lymphoma in the human immunodeficiency virus disease has not been systematically reviewed. We studied 25 patients with both human immunodeficiency virus infection and cutaneous presentations of lymphoma, using immunohistochemistry and in situ hybridization for Epstein-Barr virus. Results: Two groups of patients were discerned: (1) those with conditions similar to mycosis fungoides or Sezary syndrome with an indolent course (n=8) and (2) those with nodules or papules, greater immunosuppression, a rapid clinical course, and large cell lymphoma seen on biopsy specimens (n=17). The epidermotropic lymphomas were of T-cell lineage and CD30 - . Thirteen of the large cell lymphomas were also of the T-cell type, and 71% were CD30 + . Epstein-Barr virus was absent in the epidermotropic lymphomas, but it was present in 73% of the nonepidermotropic cases. Conclusions: Two forms of human immunodeficiency virus-associated cutaneous lymphoma were found: indolent disease resembling mycosis fungoides or Sezary syndrome and large cell lymphomas with a poor prognosis, whose cells often had a CD30 + T-cell phenotype and harbored the Epstein-Barr virus. (Arch Dermatol. 1995;131:1281-1288)

Large-cell transformation following detection of minimal residual disease in cutaneous T-cell lymphoma: molecular and in situ analysis of a single neoplastic T-cell clone expressing the identical T-cell receptor.

Abstract: PURPOSEOne of the unique characteristics of cutaneous T-cell lymphoma (CTCL) is its ability to undergo cytologic transformation in which the malignant T cells develop the morphologic appearance of a large-cell lymphoma. Reported to occur in up to 20% of advanced cases, large-cell transformation (LCT) is associated with an aggressive clinical course. Little is known about the risk factors or the molecular mechanisms of LCT. Before current immunohistochemical and molecular techniques, it was not possible to determine if LCT represented changes of the initial neoplastic T-cell clone or, in fact, was a distinct second malignancy. The goal of this study was to define the clonal evolution of LCT in CTCL.PATIENTS AND METHODSPolymerase chain reaction (PCR) amplification of T-cell receptor-beta (TCR-beta) gene rearrangements and immunohistochemistry with monoclonal antibodies to TCR-V beta regions were used as markers of T-cell clonality to analyze the skin and peripheral blood of a patient with CTCL and LCT.RESUL...

p53 and K-ras in radon-associated lung adenocarcinoma.

Abstract: Mutations in the p53 tumor suppressor gene and the K-ras proto-oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare p53 codon 249 mutation (AGG(ARG) to ATG(MET) transversion) was present in 31% of a series of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is a histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors from very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners.

Anaplastic large cell lymphoma: Update of findings

Abstract: The problem of anaplastic large cell lymphoma (ALCL) is extensively reviewed by depicting the clinical, pathological and biological characteristics of the four main varieties of ALCL: common, Hodgkin's like/Hodgkin-related, lympho-histiocytic, and giant-cell rich. Special emphasis is given to the differential diagnosis between ALCL Hodgkin like and Hodgkin's disease in the light of possible therapeutical differences.