Jing Qin

Primary follicular lymphoma of the gastrointestinal tract: A clinical and pathologic study of 26 cases

Although the gastrointestinal tract represents the most common site of extranodal lymphoma, primary follicular lymphoma of the gastrointestinal tract is an uncommon and poorly defined disease. We report the clinical and pathologic features of 26 patients with primary gastrointestinal follicular lymphoma. Ten of 26 patients (38.5%) were stage IIE, and 16 patients (61.5%) were stage IE. Of the 26 patients, 13 were female and 13 were male. The age range was 26–81 years (median 54.5 years). Abdominal pain was the most common presenting symptom, seen in 12 of 24 patients (50%). Nodularity of the mucosal surface was the most common endoscopic finding, seen in 10 of 14 patients (71.4%). The majority of cases (22 of 26, 84.6%) involved small bowel, four involved colorectum alone, and two involved the ileocecal valve. Within the small bowel the duodenum was the most commonly involved site (10 cases). Transmural involvement by follicular lymphoma was identified in 11 of the 16 patients who underwent surgical resection; five showed involvement of mucosa and submucosa only. The most common histologic grade was grade 1. Thirteen of 26 cases were grade 1, ten grade 2, and three grade 3. Twenty-one of 26 cases showed a predominantly follicular growth pattern, four mixed follicular and diffuse, and one predominantly diffuse. All cases were positive for CD20 and BCL2 and negative for CD3, CD5, CD23, CD43, and cyclin D1. Twenty-four of 26 were positive for CD10. Four of four cases showed cytogenetic or molecular genetic evidence of t(14;18). Initial treatment modalities included surgery plus chemotherapy (nine cases), surgery alone (seven cases), chemotherapy alone (four cases), observation alone (four cases), and chemotherapy and abdominal radiation (one case). One case presented with rectal polyps and was treated with polypectomy. A complete response was observed in 15 of 22 cases that received treatment, and of the 15 cases, five recurred 27–60 months after the initial diagnosis. Recurrence and progression were associated with histologic transformation to diffuse large cell lymphoma in one case. No significant correlation was identified between treatment response and various clinical and pathologic features. Overall, none of the 26 patients died of lymphoma. One patient died of a concomitant pancreatic carcinoma. Of the remaining 25 patients, 14 were disease free and 11 were alive with disease at a mean follow-up of 43 months. The estimated 5-year disease-free survival was 62%, and median disease-free survival was 69 months. The estimated 5-year relapse-free survival was 54%, and the median relapse-free survival was 63 months.

Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-Hodgkin's lymphoma

Summary:To determine the outcome of patients with chemosensitive relapsed or primary refractory Hodgkins disease (HD) or aggressive non-Hodgkins lymphoma (NHL) whose disease progresses after autologous stem cell transplantation (ASCT), we reviewed the records of 82 patients with HD and 139 patients with NHL transplanted between 1993 and 2000. Disease progression occurred in 25 patients with HD and 66 patients with NHL, with median times to progression (TTP) of 3.8 and 5.1 months, respectively. Median survival times following ASCT failure were 26 and 7.7 months for patients with HD and NHL, respectively. The second-line international prognostic index (sIPI) and the TTP (before or after 3 months from ASCT) independently were predictive of survival for NHL patients. In addition, treatment with rituximab for patients with B cell NHL was associated with improved survival (median 28.6 vs 4.1 months, P=0.003), independent of the sIPI and TTP. Prognostic factors for patients with HD were not identified. Only two patients, one of whom was among six patients who received second autologous transplants, remain disease-free. The uniformly poor outcome associated with disease progression after ASCT should prompt efforts to assess the feasibility and utility of detecting and treating post transplant residual disease during a minimal disease state, before overt progression.

Towards identification of hereditary DNA mismatch repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient's age or other clinical characteristics.

Although the significance of immunohistochemical detection of DNA mismatch repair proteins and/or microsatellite instability testing in identifying patients at risk for germline deficiency in DNA mismatch repair genes is well established in colorectal carcinomas, the proper use of such techniques in sebaceous neoplasms, another tumor type that has been implicated in patients with hereditary DNA mismatch repair deficiency, has not been clearly defined. In this study, we stratified a series of 27 patients with 1 or more sebaceous neoplasms based on the pattern of immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2, and comparatively analyzed their clinical and pathologic characteristics, including tumor-infiltrating lymphocytes and peritumoral lymphocytic response as determined by immunohistochemical staining for CD3. The study tissue samples included 30 sebaceous carcinomas, 14 sebaceous adenomas, and 7 sebaceous hyperplasias, along with 8 concurrent nonsebaceous lesions from 6 patients. Overall, 12 of the 27 (44%) patients showed abnormal IHC staining with mismatch repair proteins in their sebaceous tumors, the most commonly seen abnormality being concurrent loss of MSH2 and MSH6 (8/12, 67%). Sebaceous adenomas and carcinomas occurring in the same patients showed an identical staining pattern, as did hereditary nonpolyposis colorectal cancer-related nonsebaceous tumors in the same patients. When compared with cases that had normal expression of the mismatch repair proteins, cases with abnormal expression tended to be younger (median age, 56.5 y vs. 68 y), more likely to involve sites outside the head and neck (9/12 vs. 0/15), and more likely to have synchronous or metachronous visceral malignancies (8/12 vs. 3/15) and a positive family history. Furthermore, sebaceous tumors with abnormal expression had significantly higher CD3-positive tumor-infiltrating lymphocytes and peritumoral lymphocytic response. Thus, all these factors (age less than 60 y, involvement of nonhead and neck sites, visceral malignancy, family history fulfilling at least Bethesda guidelines, and lymphocytic infiltration) bore informative value in predicting abnormal expression of DNA mismatch repair proteins. However, their sensitivity was only modest, being 58%, 75%, 67%, 78%, and 75%, respectively. On such a premise, given that sebaceous neoplasms are only infrequently encountered, and that immunohistochemistry is easily available and reasonably reliable, we recommend that, when there exists a desire to identify hereditary DNA mismatch repair deficiency, routine immunohistochemical detection of DNA mismatch repair proteins be performed in all sebaceous neoplasms regardless of patients age or other clinical characteristics.

Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease

The prognostic significance of CD20 positive classical Hodgkins disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan–Kettering Cancer Center (MSKCC) were retrospectively identified (5/92–11/00); the samples were immunostained, and clinical data ascertained. Cases were re‐reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20+ (11%); 220 CD20−. All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow‐up of 29·2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time‐to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age ≥45 years. TTF was significantly poorer for ABVD‐treated patients with CD20+ cHD as compared with CD20− cHD. Among 167 patients treated at MSKCC, both TTF (P < 0·0001) and OS (P = 0·017) were significantly decreased in CD20+ patients as compared with CD20− cHD. CD20+ cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.

Macrophage-Derived Chemokine Expression in Classical Hodgkin's Lymphoma: Application of Tissue Microarrays

Hodgkins disease (HD) is a lymphoid malignancy characterized by the presence of Reed-Sternberg (RS) and Hodgkins 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-Hodgkins 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.

Rituximab for aggressive non-Hodgkin's lymphomas relapsing after or refractory to autologous stem cell transplantation

PURPOSEThe median survival for aggressive non-Hodgkins lymphomas relapsing after or refractory to high-dose therapy and autologous stem cell transplantation therapy is 6.2 months. In these cases, there is limited salvageability with the use of conventional therapy. The purpose of this retrospective analysis was to evaluate single-agent rituximab as treatment for aggressive non-Hodgkins lymphomas in these cases. PATIENTS AND METHODSBetween January 1997 and February 2000, we treated 17 patients with aggressive non-Hodgkins lymphomas whose disease was refractory to, or relapsed after, autologous stem cell transplantation. Treatment consisted of rituximab, 375 mg/m2 as a single agent for four weekly doses. Thirteen patients had diffuse large B-cell lymphoma, and four patients had mantle cell lymphoma. The median time from autologous stem cell transplantation to relapse was 10 months (range, 2–40 months). The median number of prior therapies, including autologous stem cell transplantation, was three (range, 2–6). RESULTSThe overall response rate to rituximab was 53%, and there were four complete responses and five partial responses. Seven of 13 patients with diffuse large B-cell lymphoma (three complete responses, four partial responses) responded, and two of four patients with mantle cell lymphoma (one complete responses, one partial responses) responded. The median progression-free survival for all responders was 13 months (range, 6–18 months). Four responders (two complete responses, two partial responses) were re-treated with a second course of rituximab for disease recurrence and responded to further antibody therapy. Rituximab was well tolerated with no serious adverse events. DISCUSSIONRituximab is effective and well-tolerated palliative treatment for aggressive non-Hodgkins lymphomas that relapse after or is refractory to autologous stem cell transplantation.

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

Summary: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 μg/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 × 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.

Molecular cytogenetic analysis of follicular lymphoma (FL) provides detailed characterization of chromosomal instability associated with the t(14;18)(q32;q21) positive and negative subsets and histologic progression

We analyzed a cohort of 61 follicular lymphomas (FL) with an abnormal G-banded karyotype by spectral karyotyping (SKY) to better define the chromosome instability associated with the t(14;18)(q32;q21) positive and negative subsets of FL and histologic grade. In more than 70% of the patients, SKY provided additional cytogenetic information and up to 40% of the structural abnormalities were revised. The six most frequent breakpoints in both SKY and G-banding analyses were 14q32, 18q21, 3q27, 1q11–q21, 6q11–q15 and 1p36 (15–77%). SKY detected nine additional sites (1p11–p13, 2p11–p13, 6q21, 8q24, 6q21, 9p13, 10q22–q24, 12q11–q13 and 17q11–q21) at an incidence of >10%. In addition to the known recurring translocations, t(14;18)(q32;q21) [70%], t(3;14)(q27;q32) [10%], t(1;14)(q21;q32) [5%] and t(8;14)(q24;q32) [2%] and their variants, 125 non-IG gene translocations were identified of which four were recurrent within this series. In contrast to G-banding analysis, SKY revealed a greater degree of karyotypic instability in the t(14;18) (q32;q21) negative subset compared to the t(14;18)(q32;q21) positive subset. Translocations of 3q27 and gains of chromosome 1 were significantly more frequent in the former subset. SKY also allowed a better definition of chromosomal imbalances, thus 37% of the deletions detected by G-banding were shown to be unbalanced translocations leading to gain of genetic material. The majority of recurring (>10%) imbalances were detected at a greater (2–3 fold) incidence by SKY and several regions were narrowed down, notably at gain 2p13–p21, 2q11–q21, 2q31–q37, 12q12–q15, 17q21–q25 and 18q21. Chromosomal abnormalities among the different histologic grades were consistent with an evolution from low to high grade disease and breaks at 6q11–q15 and 8q24 and gain of 7/7q and 8/8q associated significantly with histologic progression. This study also indicates that in addition to gains and losses, non-IG gene translocations involving 1p11–p13, 1p36, 1q11–q21, 8q24, 9p13, and 17q11–q21 play an important role in the histologic progression of FL with t(14;18)(q32;q21) and t(3q27).

MUC-1 mucin protein expression in B-cell lymphomas.

We have recently shown that MUC1, mapped to the chromosomal band 1q21, is rearranged or amplified in 15% of B-cell lymphomas and that rearrangement led to over-expression of MUC-1 mucin in a case of diffuse large B-cell lymphoma (DLBCL). To determine the incidence of MUC-1 mucin expression and its clinical significance in B-cell lymphomas, we investigated a panel of 113 cases by immunohistochemistry (IHC). MUC-1 mucin expression was detected in the majority of cases (92.9%), with moderate to high levels noted in 50.4% of all histologic subsets comprising DLBCL (82 cases), follicular lymphoma (FL) (15 cases), FL with transformation to DLBCL (4 cases), and other B-cell lymphomas (12 cases). No statistically significant correlation was found between MUC-1 mucin expression and MUC1 genomic status (amplification/rearrangement) evaluated by Southern blot analysis, and 1q21 abnormality by karyotypic analysis. For all cases, MUC-1 mucin expression correlated with a previous history of lymphoma (p=0.003).

CHOP with High Dose Cyclophosphamide Consolidation versus CHOP Alone as Initial Therapy for Advanced Stage, Indolent Non-Hodgkin's Lymphomas

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkins lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1,4,7,10): cyclophosphamide 750 mg/m 2 IV, doxorubicin 50 mg/m 2 IV, vincristine 1.4 mg/m 2 IV (2 mg capped dose) and prednisone 100 mg PO × 5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m 2 IV for 3 doses with G-CSF (weeks 13,15,17) or 2 additional cycles of CHOP (weeks 13,16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkins lymphomas.