Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification.

BACKGROUND: The World Health Organization (WHO) classification of hematologic malignancies, published in 2000, was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. METHODS: We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. RESULTS: Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P=NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P=NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitt's lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. CONCLUSIONS: Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care.

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation.

Autologous stem cell transplantation (SCT) with high-dose melphalan (HDM, 200 mg/m2) is the most effective therapy for multiple myeloma. To determine the feasibility of combining carmustine (300 mg/m2) with HDM, we enrolled 49 patients with previously treated Durie-Salmon stage II/III myeloma (32M/17W, median age 53) on a phase I/II trial involving escalating doses of melphalan (160, 180, 200 mg/m2). The median beta2-microglobulin was 2.5 (0-9.3); marrow karyotypes were normal in 88%. The phase I dose-limiting toxicity was > or =grade 2 pulmonary toxicity 2 months post-SCT. Other endpoints were response rate and progression-free survival (PFS). HDM was safely escalated to 200 mg/m2; treatment-related mortality was 2% and > or =grade 2 pulmonary toxicity 10%. The complete (CR) and near complete (nCR) response rate was 49%. With a median post-SCT follow-up of 2.9 years, the PFS and overall survival (OS) post-SCT were 2.3 and 4.7 years. PFS for those with CR or nCR was 3.1 years while for those with stable disease (SD) it was 1.3 years (P=0.06). We conclude that carmustine can be combined with HDM for myeloma with minimal pulmonary toxicity and a high response rate.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial.

Multiple myeloma (MM) is an incurable hematologic malignancy for which autologous hematopoietic stem cell transplantation (HCT) is a standard therapy. The optimal method of stem cell mobilization is not defined. We evaluated intravenous melphalan (60 mg/m2), the most effective agent for MM, and G-CSF (10 microg/kg/day) for mobilization. End points were safety, adequacy of CD34+ collections, MM response, and contamination of stem cell components (SCC). In total, 32 patients were mobilized. There were no deaths or significant bleeding episodes; 14 patients (44%) required hospitalization for neutropenic fever. Median days of grade 3 or 4 neutropenia or thrombocytopenia were 7 (2-20) and 8 (3-17). Median mobilization days, CD34+ cells/kg and total leukaphereses were 16 (12-30), 12.1 million (2.6-52.8), and 2 (1-5) respectively. Four patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in five leukaphereses. Reduction in myeloma was seen in 11 patients (34%) with 3 (9%) achieving complete response; 15 (47%) maintained prior responses. Estimated MM contamination per SCC (N=48) was 0.0009% (range 0-0.1) and 0.21 x 10(4) cells per kg (range 0-41.2). Increased contamination was associated with increased patient age. This strategy for mobilization is feasible, frequently requires hospitalization and transfusion, and controls disease in most patients.

CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients.

BACKGROUND: Plasmablastic lymphoma (PBL) has been described as a rapidly progressive and almost invariably fatal CD20- VS38c+ diffuse large-cell lymphoma with plasmablastic features, almost exclusively involving the jaw and oral mucosa in HIV-positive patients. METHODS: From 2001 to 2003 we evaluated 12 men with PBL, and report the pathology, clinical findings, treatment and outcome. Six of 12 were HIV-positive while among the others, one was post-renal transplant, one had ulcerative colitis and four had no known immunodeficiency. RESULTS: Tumor growth pattern, in general, showed cohesiveness and a starry-sky pattern; the morphology varied from typical plasmablastic to centroblastic cells. Partial immunophenotypes were (+/total): CD138, 11 of 12 (91.7%); MIB1 10 of 11 (4+, range 75-95%); p63/VS38c, nine of 10 (90%); EBV, eight of 11 (73%); LCA(CD45), two of 12 (16.7%); HHV8/LANA, zero of 10; ALK, zero of seven; and CD20, zero of 12. Three had stage IE and nine stage IV disease. Nine of 12 had an intermediate/high International Prognostic Index or high-risk disease. Computed tomography and positron emission tomography scan in four of 12 revealed extensive bone metastases. Eight of 12 are alive after treatment, with a median follow-up of 11+ months (range 1-24). Of the HIV-positive patients, five of six are alive with a median follow-up of 17 months. CONCLUSIONS: It appears that PBL are heterogenous in terms of clinical presentation and morphology. The outcome presented here is superior to that originally reported.

The NHL-15 protocol for aggressive non-Hodgkin's lymphomas: a sequential dose-dense, dose-intense regimen of doxorubicin, vincristine and high-dose cyclophosphamide.

BACKGROUND: The NHL-15 protocol is a novel, dose-intense, dose-dense, sequential chemotherapy program developed to improve outcome in advanced, aggressive non-Hodgkin's lymphomas. PATIENTS AND METHODS: The phase II NHL-15 protocol comprised: (i) induction [doxorubicin 60 mg/m(2) i.v. on weeks 1, 3, 5 and 7 plus vincristine 1.4 mg/m(2) i.v. (no cap) on weeks 1, 2, 3, 5 and 7]; and (ii) consolidation (cyclophosphamide 3000 mg/m(2) i.v. on weeks 9, 11 and 13 plus granulocyte colony-stimulating factor 5 microg/kg subcutaneous on days 3-10 following each cyclophosphamide dose). Patients with aggressive non-Hodgkin's lymphomas (working formulation: intermediate grade or immunoblastic), bulky stage I and stages II-IV, were eligible. RESULTS: There are 165 eligible patients with a 6.9-year median follow-up (range 0.5-141 months) and a median age of 48 years. For the entire group, 72.1% achieved complete remission, and at 5 years disease-free survival was 57.8% and overall survival (OS) was 62.2%. Ideal dose delivery was >90%. Acute and late toxicities of treatment were manageable and acceptable. Toxic death on treatment was 2.4%. When the diffuse large cell lymphoma histologies were grouped according to the International Prognostic Index (IPI), complete remission and OS in the low-intermediate (LI), and high-intermediate (HI) risk groups were improved by 5%-15% compared with historical CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). This improvement was also noted for LI and HI risk groups in the age-adjusted (aa)IPI analysis for patients < or =60 years of age. CONCLUSIONS: The NHL-15 program can be administered safely and effectively to achieve high rates of durable remission when used for the treatment of advanced stage, aggressive, non-Hodgkin's lymphomas. The 5%-15% improvement in 5-year OS compared with historical CHOP, according to the IPI/aaIPI model (in LI and HI risk groups), is encouraging. Further evaluation and prospective testing of the NHL-15 protocol appears to be warranted.

Systemic AL amyloidosis due to non-Hodgkin's lymphoma: an unusual clinicopathologic association.

Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non-Hodgkin's lymphoma (NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab-based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10-132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted.

Macrophage-derived chemokine expression in classical Hodgkin's lymphoma: application of tissue microarrays.

Hodgkin's disease (HD) is a lymphoid malignancy characterized by the presence of Reed-Sternberg (RS) and Hodgkin's cells in a background of mixed inflammatory cells and stromal reaction. Studies have documented that HD is a neoplasm associated with abnormal cytokine and chemokine production. To define the expression of macrophage-derived chemokine (MDC) in HD, 57 cases (18 lymphocyte predominant, 11 mixed cellularity, 28 nodular sclerosis) were stained for MDC by immunohistochemistry and compared with reactive lymph nodes as controls. MDC was expressed by RS cells in classical HD (CHD) and showed a distinct cytoplasmic and Golgi localization. Accumulating evidence suggests that lymphocyte-predominant HD (LPHD) represents an entity distinct from CHD, with different biological properties and clinical course. On the basis of the high level of MDC staining alone, CHD could be distinguished from LPHD (P <.001), which showed only faint staining of scattered histiocytes similar to control tissues. CHD cases with high MDC mRNA levels showed high levels of MDC protein expression by immunohistochemistry (P <.001) and significant eosinophil infiltration, suggesting that MDC may represent another molecule that plays a critical role in eosinophil recruitment. We also analyzed 102 cases of non-Hodgkin's lymphoma and normal spleen, lymph node, and thymic tissue. High levels of MDC expression were specific to CHD cases because only low levels of MDC were observed in a minor subset of LPHD, NHL or normal lymphoid tissues.

Establishment of a human cell line (SKI-DLCL-1) with a t(1;14)(q21;q32) translocation from the ascites of a patient with diffuse large cell lymphoma.

Cytogenetic abnormalities at chromosome 1q21 are among the most common second genetic events observed in Non-Hodgkin's Lymphomas and have prognostic significance. Recently, BCL9 has been cloned from a pre-B-cell lymphoblastic leukemia cell line, which carried a t(1:14)(q21;q32). However, among a panel of 39 B-cell malignancies with 1q21 translocation, only two cases showed rearrangement for the BCL9 gene. We report the establishment of a new lymphoma cell line from a patient with relapsed diffuse large cell lymphoma. This cell line SKI-DLCL-1 showed cell surface antigens identical to the original tumor and demonstrated the profile of a mature B-cell phenotype: CD19 and CD20 positive, CD5 and C10 negative. It carried a t(1;14)(q21;q32) translocation identical to the original tumor. Although the clinical presentation was an isolated effusion lymphoma, studies for HIV-1, HHV8 and EBV were all negative. Southern blot analysis demonstrated that BCL9 was not rearranged in the SKI-DLCL-1 cell line. In addition, the BCL9 gene was not over-expressed in SKI-DLCL-1 cell line. The identification of a new locus at 1q21 will help clarify the pathogenesis of B-cell malignancies with a translocation involving this locus.

Clonotypic polymerase chain reaction confirms minimal residual disease in CLL nodular PR: results from a sequential treatment CLL protocol.

Patient-tumor-specific oligonucleotides were generated for the detection of minimal residual disease (MRD) in a highly specific and sensitive clonotypic polymerase chain reaction (cPCR). The clone-specific region of highest diversity, CDR-III, was PCR amplified and sequenced. Nested CDR-III clonotypic primers were used in a semi-nested cPCR with a sensitivity of at least 1 in 10(5) cells. Patients with protocol-eligible Rai intermediate or high-risk chronic lymphocytic leukemia (CLL) received induction with fludarabine 25 mg/m(2) per day for 5 days every 4 weeks for 6 cycles, followed by consolidative high-dose cyclophosphamide (1.5, 2.25, or 3g/m(2)). cPCR was performed on peripheral blood and bone marrow mononuclear cells. All 5 patients achieving a clinical partial remission (PR) studied by cPCR were positive. Five patients achieved nodular PR (nPR) (residual nodules or suspicious lymphocytic infiltrates in a bone marrow biopsy as the sole suggestion of residual disease). Five of 5 patients with nPR were cPCR positive. In contrast, flow cytometry for CD5-CD19 dual staining and kappa--lambda clonal excess detected MRD in only 3 of the same 5 nPR patients, all of whom were cPCR positive, and immunohistochemistry detected MRD in only 1 of 4 assessable patients. Three of 7 CR patients evaluable by cPCR had MRD. Only 1 CR patient had MRD by flow cytometry; that patient was also cPCR positive. These data support the conclusions that nodular PR in CLL represents MRD and that clonotypic PCR detects MRD in CLL more frequently than flow cytometry or immunohistochemistry. (Blood. 2001;97:1929-1936)

A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.

Salvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P <.001). These results compare favorably with other series and document the feasibility and efficacy of giving uniform dose-dense and dose-intense cytoreductive chemotherapy and integrating accelerated fractionation radiotherapy into an ASCT treatment program. This prognostic model provides a basis for risk-adapted HDT.

ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).

The subset of CD30-positive anaplastic large cell lymphomas (ALCL) with the NPM-ALK gene fusion arising from the t(2;5)(p23;q35) forms a distinct clinical and prognostic entity. Recently, various cytogenetic, molecular, and protein studies have provided evidence for the existence of several types of variant ALK fusions in up to 20% of ALK+ ALCL, of which only one, a TPM3-ALK fusion resulting from a t(1;2)(q25;p23), has so far been cloned. A cryptic inv(2)(p23q35) has been described as another recurrent cytogenetic alteration involving ALK and an unidentified fusion partner in some ALCL. In a screen for variant ALK gene fusions, we identified two ALCL that were negative for NPM-ALK by reverse transcriptase-polymerase chain reaction, but were positive for cytoplasmic ALK with both polyclonal and monoclonal antibodies to the ALK tyrosine kinase domain, consistent with ALK deregulation by an alteration other than the t(2;5) Case 1 was a T-lineage nodal and cutaneous ALCL in a 52-year-old woman, and Case 2 was a T-lineage nodal ALCL in a 12-year-old girl. FISH analysis confirmed ALK rearrangement in both cases. An inverse polymerase chain reaction approach was then used to identify the ALK translocation partner in Case 1. We found an in-frame fusion of ALK to ATIC, a gene previously mapped to 2q34-q35. We then confirmed by DNA polymerase chain reaction the localization of ATIC to yeast artificial chromosome (YAC) 914E7 previously reported to span the 2q35 break in the inv(2)(p23q35). FISH analysis in Case 1 confirmed rearrangement of YAC 914E7 and fusion to ALK. The ATIC-ALK fusion was confirmed in Case 1 and also identified in Case 2 by conventional reverse transcriptase-polymerase chain reaction using ATIC forward and ALK reverse primers. ATIC encodes an enzyme involved in purine biosynthesis which, like other fusion partners of ALK, is constitutively expressed and appears to contain a dimerization domain. ATIC-ALK fusion resulting from the inv(2)(p23q35) thus provides a third mechanism of ALK activation in ALK+ ALCL.

Large cell non-Hodgkin lymphoma of childhood: Analysis of 78 consecutive patients enrolled in 2 consecutive protocols at the Memorial Sloan-Kettering Cancer Center.

BACKGROUND: The authors report a study of pediatric patients with advanced diffuse large cell lymphoma (DLCL) who were treated with 2 consecutive regimens, LSA2-L2 and LSA4, over a 25-year-period at the Memorial Sloan-Kettering Cancer Center. They also describe a comparative analysis of two subgroups retrospectively identified as having CD30 positive (+) anaplastic large cell lymphoma (ALCL) and CD30 negative (-) DLCL. To the authors' knowledge, this study represents the longest follow-up on the largest series of uniformly treated pediatric DLCL patients reported to date. METHODS: A total of 78 consecutive patients were treated for Stage III/IV DLCL. Immunophenotypic data were obtained retrospectively for 52 patients using a panel of monoclonal antibodies against CD30, CD15, CD45, CD45Ro, CD43, epithelial membrane antigen, CD5, BCL-2, cyclin-D, and p53. RESULTS: A disease free survival rate of 72% in patients with advanced stage DLCL using the LSA2-L2 and LSA4 regimens. Of the 78 treated patients, 56 are alive and without evidence of disease with a median follow-up of 120 months (range, 24-312 months). The recurrence rate was significantly higher in the CD30+ ALCL subgroup (33%) than in the CD30- DLCL group (0.04%). Of 52 patients for whom immunophenotypic data were available, 28 had disease of B-cell lineage, 24 had disease of T-cell/null phenotype, 19 were CD30+ (36. 5%), 18 had disease of T-cell phenotype, and 1 had disease of B-cell lineage. CONCLUSIONS: The CD30- DLCL cases mostly were of B-cell lineage, had a small risk of treatment failure, and did not develop a recurrence off therapy. A distinct clinical pattern was identified for the CD30+ ALCL group; although these tumors were of T-cell lineage and had a significantly higher rate of late recurrences (median follow-up of 24 months) they all were salvageable. Based on the findings of the current study, the authors propose that T-cell CD30+ ALCL be addressed in the future according to equal dose intensity regimens in induction therapy, as is done for B-cell lymphomas; prolonged periods of maintenance chemotherapy, as is done for T-cell lymphoblastic lymphomas; and no central nervous system prophylaxis beyond the induction period unless other recognized risk factors are present.

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas.

Cytogenetic analysis was performed on 363 biopsy specimens with histologically confirmed diffuse large B-cell lymphoma (DLBCL), consecutively ascertained at the Memorial Sloan-Kettering Cancer Center, New York, between 1984 and 1994. Among 248 samples successfully karyotyped, clonal chromosomal abnormalities were noted in 215 (87%). The salient cytogenetic features of DLBCL from this analysis comprised the following. Breakpoints clustered, in decreasing frequency, at 10 recurring sites: 14q32, 18q21, 1q21, 3q27, 1p36, 8q24, 3p21, 6q21, 1p22, and 22q11. Of these, deletion breaks affecting bands 3p2 and 1p22 and translocation breaks affecting bands 14q32, 3q27, and 1q2 were frequent and distinctive for this subset of lymphomas. Translocations affecting band 14q32 were noted in 110 cases (51%) of which 42 (20%) had t(14;18)(q32;q21), 21 (10%) had t(8;14)(q24;q32) or t(8;22)(q24;q11), 14 (6.5%) had t(3;14)(q27;q32) or t(3;22)(q27;q11), and 33 (15%) had other rearrangements of 14q32. Among 144 new translocations detected in the entire group, the breakpoints in 19 were recurrent and clustered at three sites: 1q21, 3q27, and 14q32. Regions of common cytogenetic deletions were identified at 11 sites, 1p36, 1p33-34, 1p31, 1q32, 3p25-26, 3p21, 3q21, 6q15, 6q21, 6q23-24, and 7q32, suggesting possible loss of candidate tumor suppressor genes associated with DLBCL development. Of these, only those at 6q21, 6q23, and 7q32 have previously been described in lymphoid neoplasms. The group of DLBCL with translocations affecting band 14q32 showed a significantly different pattern of additional cytogenetic changes compared to the group lacking such translocation. This new comprehensive cytogenetic characterization provides the basis for investigations aimed at identifying molecular mechanisms as well as the clinical impact of cytogenetic changes in DLBCL.

The management of unicentric and multicentric Castleman's disease: a report of 16 cases and a review of the literature.

BACKGROUND: Castleman's disease (CD), or angiofollicular lymph node hyperplasia, creates both diagnostic and therapeutic dilemmas for most physicians. For patients with this rare and poorly understood disease, the optimal therapy is unknown. The authors report their experience during the years 1986-1997 with this uncommon clinicopathologic entity. METHODS: Sixteen patients with a histologic diagnosis of CD were identified in the pathology database. Unicentric disease was defined as a solitary mass. Multicentric disease compromised patients with widespread lymphadenectomy. Clinical, radiologic, and laboratory data were analyzed to evaluate treatment response. RESULTS: The study group consisted of 16 patients classified into 3 clinicopathologic groups: hyaline-vascular, plasma cell, and "mixed." Of those patients who underwent complete surgical excision of a unicentric hyaline-vascular CD mass (n = 8), all remain symptom free without clinical or radiographic recurrence. Two patients remain asymptomatic following partial resection or radiation therapy for an unresectable unicentric hyaline-vascular CD mass. Two patients with multicentric hyaline-vascular CD are currently in complete remission following adjuvant therapy. Multicentric plasma cell CD was present in a single patient. This patient (who underwent surgical and systemic therapy) died of disease within 4 months of presentation. Three patients with unicentric hyaline-vascular/plasma cell-CD remain symptom free following either complete resection or observation. CONCLUSIONS: The authors recommend surgical resection for patients with the unicentric variant of CD. Surgical removal of a unicentric mass of hyaline-vascular or hyaline-vascular/plasma cell type is curative. Partial resection, radiotherapy, or observation alone may avoid the need for excessively aggressive therapy. Patients with multicentric disease, either hyaline-vascular or plasma cell type, do not benefit from surgical management and should be candidates for multimodality therapy, the nature of which has yet to be defined.

Extramedullary hematopoiesis mimicking metastatic lung carcinoma.

Extramedullary hematopoiesis is a rare condition defined as the appearance of hematopoietic elements outside of the bone marrow, which occurs primarily in patients with chronic myeloproliferative disorders or congenital hemolytic anemias. We report a patient who presented with a left lower lobe lung carcinoma and right paravertebral and left pleural masses, initially thought most consistent radiographically with inoperable metastatic disease, until biopsies of the paravertebral and pleural masses established the presence of extramedullary hematopoiesis. The left lower lobe neoplasm was subsequently resected uneventfully.

Immunohistochemical analysis of murine CD95/Fas/Apo-1 receptor and its ultrastructural distribution in the thymus.

CD95/Fas/Apo-1 is a cell surface receptor that, upon contact with its ligand, induces cells to die by apoptosis. In view of the importance of Fas receptor (FasR) in immunologic tolerance, an immunohistochemical analysis of FasR expression was performed in the lymphoid and certain parenchymal tissues of normal and mutant MRL/lpr mice using a rabbit polyclonal anti-Fas receptor antibody. FasR was expressed by immunoperoxidase (IP) in the cortex and at the corticomedullary junction of the thymus of normal mice. By immunoelectron microscopy FasR was detected on the cell membrane of normal thymocytes. In MRL/lpr mice, FasR protein expression could not be clearly detected. FasR protein expression was not detected in the heart, liver or ovary by IP, presumably reflecting the low number of receptors in these tissues.

A case-control study of endometrial cancer in relation to reproductive, somatometric, and life-style variables.

A hospital-based case-control study of cancer of the endometrium was conducted in Athens, Greece, from 1992 to 1994. The cases were 145 women residents of Greater Athens with histologically confirmed incident cancer of the endometrium, operated in the two cancer hospitals of the Greater Athens area or the major University Department of Obstetrics and Gynecology. Controls were 298 women residents of Greater Athens hospitalized for bone fractures or other orthopedic conditions in the accident hospital of Greater Athens. The data were analyzed by modeling through multiple logistic regression. The risk of endometrial cancer decreased with the number of livebirths (p for trend < 0.01), with early age at menopause (p = 0.03), and with later age at menarche (p = 0.11), whereas miscarriages and induced abortions were clearly unrelated. There were nonsignificant relations of disease risk with smoking (inverse), alcohol (inverse), and menopausal estrogens (positive), whereas oral contraceptive use was too uncommon to allow meaningful study. The lower risk of the disease associated with current occupations requiring manual activity (p = 0.03) and the lower, although not significantly so (p = 0.36), energy intake of cases in comparison to controls suggest that physical inactivity could be an important risk factor for endometrial cancer. Women with endometrial cancer were significantly taller than control women (p = 0.02). The latter results indicate that excess energy intake in early life, leading to higher attained stature, and excessive energy intake in later life, on account of physical inactivity and leading to higher body weight, converge in increasing the risk for endometrial cancer.

Coexistence of renal cell carcinoma and malignant lymphoma. A causal relationship or coincidental occurrence?

BACKGROUND: Secondary malignant neoplasms are increasingly being observed in cancer populations and a considerable amount of data have accumulated in the literature. Among the secondary malignant neoplasms that occur with a higher incidence in cancer patients are lymphomas and renal cell carcinoma (RCC), as well as melanoma, lung/bronchus carcinoma. METHODS: The authors analyzed the patient population at the Memorial Sloan-Kettering Cancer Center in New York City between 1985 and 1995 for coexisting carcinomas, and identified 15 patients who had both RCC and malignant lymphoma among a total of 1262 patients with RCC and 1660 patients with malignant lymphoma. The occurrence and time of diagnosis of both malignant neoplasms and their clinical features, types, and stages, as well as short term follow-up, results, are presented. RESULTS: The data show a greater than coincidental coexistence of RCC and malignant lymphoma (P < 0.01). In addition, there was a significant increase in the number of patients with both melanoma and RCC (P < 0.01), as well as melanoma and malignant lymphoma (P < 0.01). No significant increase was found in cases of coexisting RCC or malignant lymphoma with either lung/bronchus carcinoma or colorectal carcinoma (P > 0.05). CONCLUSIONS: Causes of this increased coexistence may include a genetic predisposition to cancer, similar immune mechanisms associated with these neoplasms, closer scrutiny of this group of patients, or a combination of these factors. Studies are underway to elucidate a common genetic component in these patients.