Nissim Haim

18F-FDG Avidity in Lymphoma Readdressed: A Study of 766 Patients

PET/CT with 18F-FDG is an important noninvasive diagnostic tool for management of patients with lymphoma, and its use may surpass current guideline recommendations. The aim of the present study is to enlarge the growing body of evidence concerning 18F-FDG avidity of lymphoma to provide a basis for future guidelines. Methods: The reports from 18F-FDG PET/CT studies performed in a single center for staging of 1,093 patients with newly diagnosed Hodgkin disease and non-Hodgkin lymphoma between 2001 and 2008 were reviewed for the presence of 18F-FDG avidity. Of these patients, 766 patients with a histopathologic diagnosis verified according to the World Health Organization classification were included in the final analysis. 18F-FDG avidity was defined as the presence of at least 1 focus of 18F-FDG uptake reported as a disease site. Nonavidity was defined as disease proven by clinical examination, conventional imaging modalities, and histopathology with no 18F-FDG uptake in any of the involved sites. Results: At least one 18F-FDG–avid lymphoma site was reported for 718 patient studies (94%). Forty-eight patients (6%) had lymphoma not avid for 18F-FDG. 18F-FDG avidity was found in all patients (100%) with Hodgkin disease (n = 233), Burkitt lymphoma (n = 18), mantle cell lymphoma (n = 14), nodal marginal zone lymphoma (n = 8), and lymphoblastic lymphoma (n = 6). An 18F-FDG avidity of 97% was found in patients with diffuse large B-cell lymphoma (216/222), 95% for follicular lymphoma (133/140), 85% for T-cell lymphoma (34/40), 83% for small lymphocytic lymphoma (24/29), and 55% for extranodal marginal zone lymphoma (29/53). Conclusion: The present study indicated that with the exception of extranodal marginal zone lymphoma and small lymphocytic lymphoma, most lymphoma subtypes have high 18F-FDG avidity. The cumulating evidence consistently showing high 18F-FDG avidity in the potentially curable Burkitt, natural killer/T-cell, and anaplastic large T-cell lymphoma subtypes justifies further investigations of the utility of 18F-FDG PET in these diseases at presentation.

Prevention of Gonadal Damage during Cytotoxic Therapy

Infertility represents one of the main remote sequelae of cytotoxic chemotherapy given for various malignant diseases. The impairment of gonadal function after cytotoxic chemotherapy is more frequent in the male than in the female. Because dividing cells are more sensitive to the cytotoxic effects of alkylating agents than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis by gonadotropin-releasing hormone (GnRH) agonists would render the germinal epithelium less susceptible to the cytotoxic effects of chemotherapy. This hypothesis has not been thoroughly clinically tested until recently, although several investigators have demonstrated that GnRH-agonistic analogues (GnRH-a) inhibit chemotherapy-induced ovarian follicular depletion in the rat and Rhesus monkeys. Based on this rationale, we have undertaken a prospective evaluation to determine whether GnRH-a administration during combination chemotherapy for Hodgkins and non-Hodgkins lymphoma could prevent posttreatment ovarian damage in women by inducing a temporary prepubertal hormonal milieu. While over 93% of the surviving patients in the GnRH-a and chemotherapy group resumed spontaneous ovulation and menses, less than 40% of the women in the control group of chemotherapy without the GnRH-a cotreatment resumed normal ovarian cyclic activity. More than 60% of the women experienced premature ovarian failure (POF) in the chemotherapy alone group. Our preliminary results suggest that GnRH-a cotreatment protects against POF during cytotoxic chemotherapy. The GnRH-a and chemotherapy cotreatment may be also suggested for young women treated by cyclophosphamide pulse therapy or other gonadotoxic treatments for systemic lupus erythematosus, organ transplantation and other autoimmune diseases. The technology of cryopreservation of human ova for future fertility in these patients awaits clinical validation and substantiation. This review discusses possibilities to prevent gonadal damage induced by cytotoxic therapy and presents the clinical data currently available.

Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism

PURPOSE Cancer patients have an increased risk for venous thromboembolism. Because activated protein C resistance is a common risk factor for venous thromboembolism, we prospectively evaluated the activated protein C sensitivity ratio and factor V Leiden mutation in cancer patients with and without venous thromboembolism. SUBJECTS AND METHODS We studied 55 consecutive cancer patients with deep vein thrombosis, 58 cancer patients with no history of venous thromboembolism, 54 patients with venous thromboembolism without malignancy, and 56 healthy controls. The presence of factor V Leiden mutation was determined by polymerase chain reaction and allele specific restriction digestion. The activated protein C sensitivity ratio was expressed as the ratio of activated partial thromboplastin times measured in the presence and absence of activated protein C; a ratio <2.0 in patients who did not have factor V Leiden was considered to indicate acquired activated protein C resistance. RESULTS The prevalence of factor V Leiden mutation in cancer patients with thromboembolism (1 of 55, 2%) did not differ significantly from those in cancer patients without thromboembolism (4 of 58, 7%) or normal controls (2 of 56, 4%), but was significantly lower than that of patients with thromboembolism without cancer (18 of 54, 33%, P <0.001). The prevalence of acquired activated protein C resistance was significantly greater in cancer patients with thromboembolism (29 of 54, 54%, P = 0.001) compared with the other groups: 9 of 54 (17%) in cancer patients without thromboembolism, 7 of 36 (19%) in patients with thromboembolism without cancer, and none of the normal controls. CONCLUSION Although factor V Leiden is not a major risk factor for thrombosis in cancer patients, acquired activated protein C resistance is common and may contribute to the thrombotic tendency in these patients.

Non-Hodgkin's lymphoma presenting with spinal epidural involvement

Cord compression was noted at presentation in 10 of 453 (2.2%) previously untreated non‐Hodgkins lymphoma patients seen at the Northern Israel Oncology Center between 1968 and 1983. A prodromal phase of local back pain occurred in eight patients, persisting up to 1 year, followed by a second phase of rapidly progressive signs of cord compression. Five of the ten patients presented with primary spinal epidural involvement (Stage IE), whereas the others had Stage IIE and IIIE (one patient each) and Stage IV, with bone and bone marrow involvement (three patients). All patients had unfavorable histologic diagnoses, mostly of the intermediate grade malignancy types according to the Working Formulation. The patients were treated by radiotherapy (two patients), chemotherapy (three patients), or both modalities (five patients). Seven of the ten patients achieved complete remission, but four of them have subsequently had relapses (two patients in bone, one in central nervous system, and one in mediastinum). The 5‐year actuarial survival and 3‐year relapse‐free survival were 66% and 32%, respectively. Median survival has not been reached after a mean follow‐up of 34 months. Non‐Hodgkins lymphoma with spinal epidural involvement at presentation is an aggressive disease. An intensive treatment combining irradiation with chemotherapy, and surgery as needed, is suggested in order to achieve good local response and long‐term survival.

FDG avidity and PET/CT patterns in primary gastric lymphoma.

PurposeThe use of 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in primary gastric lymphoma (PGL) is challenging due to physiologic FDG activity in the stomach and variability in the degree of uptake in various histologic subtypes. This study assesses FDG avidity and PET/CT patterns in newly diagnosed PGL.MethodsSixty-two PET/CT studies of newly diagnosed PGL were reviewed (24 low-grade mucosa-associated lymphoid tissue [MALT], 38 aggressive non-Hodgkin’s lymphoma [AGNHL]). FDG avidity, patterns (focal/diffuse), and intensity (visually vs. the liver and SUVmax) were assessed and compared to 27 controls. Gastric CT abnormalities and extragastric sites were recorded.ResultsGastric FDG uptake was found in 55/62 (89%) PGL (71% MALT vs. 100% AGNHL, p < 0.001) and 63% controls. A diffuse pattern was found in 60% PGL (76% MALT vs. 53% AGNHL, p = NS) and 47% controls. FDG uptake higher than liver was found in 82% PGL (58% MALT vs. 97% AGNHL, p < 0.05) and 63% controls. SUVmax in FDG-avid PGLs was 15.3 ± 11.7 (5.4 ± 2.9 MALT vs. 19.7 ± 11.5 AGNHL, p < 0.001) and 4.6 ± 1.4 in controls. CT abnormalities were found in 79% PGL (thickening, n = 49; ulcerations, n = 22). Extra-gastric FDG-avid sites were seen in none of MALT, but 61% of AGNHL (nodal, n = 18; nodal and extranodal, n = 5).ConclusionsFDG avidity was present in 89% of PGLs, including all patients with AGNHL but only 71% of MALT. FDG uptake can be differentiated, in particular in AGNHL-PGL, from physiologic tracer activity by intensity but not by pattern. Extragastric foci on PET and structural CT abnormalities are additional parameters that can improve PET/CT assessment of PGL. Defining FDG avidity and PET/CT patterns in AGNHL and a subgroup of MALT-PGL before treatment may be important for further monitoring therapy response.

Intermediate and High-Grade Gastric Non-Hodgkin's Lymphoma: A Prospective Study of Non-Surgical Treatment with Primary Chemotherapy, with or without Radiotherapy

The role of surgery as initial treatment in gastric lymphoma remains controversial. We have prospectively evaluated a stomach conservation strategy in histologically aggressive gastric lymphoma, using primary adriamycin-containing chemotherapy, followed by involved-field radiotherapy in patients with limited disease. Twenty-six patients (median age 69 years) were entered in this study; 15 had stage I disease, 7 had stage II disease and 4 had stage IV disease. The chemotherapy combinations were CHOP (18 patients) and ProMACE/MOPP (8 patients). Radiotherapy was given to 11 patients. Of the 24 patients evaluated for response, 18 (75%) achieved endoscopically-confirmed complete response and 4 (17%) partial response. During follow-up (median 22 months), none of the complete responders developed recurrent lymphoma. Gastric resection was performed in 1/26 patients who did not respond to primary chemotherapy. There were no cases of perforation, but three patients (12%) developed acute gastro-intestinal bleeding a few days after the onset of chemotherapy, one of whom required a surgical devascularization procedure. There was no treatment-related mortality. These data further support the non-surgical approach in histologically aggressive gastric lymphoma, using primary chemotherapy with or without radiation therapy.

Single-photon emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake

PURPOSE To assess the role of quantitative gallium citrate (Ga 67) single-photon emission computed tomography (SPECT) in differentiating lymphoma from benign hilar uptake, concentrations of Ga 67 in 29 sites of documented lymphoma and in 75 benign lesions were compared. PATIENTS AND METHODS One hundred seven thoracic Ga 67 SPECT studies obtained in 101 consecutive lymphoma patients were reviewed. Fifty-nine studies detected Ga 67 uptake in the hilar and or mediastinal regions. Forty-eight studies showed no such abnormality. The concentration of Ga 67 in the thoracic lesions was measured using a quantitative SPECT technique and its nature was determined by correlation with computed tomographic (CT) scans and follow-up evaluation of the sites. RESULTS In 20 of 59 abnormal studies (34%), there was lymphoma in the hilar and or mediastinal regions. In the remaining 39 abnormal studies (66%), Ga 67 uptake was benign. There were 29 sites of lymphoma and 75 benign lesions. The concentration of Ga 67 in lymphoma was significantly higher than in benign hilar uptake (13.2 +/- 5.4 %ID/mL x 10(-3) v 5.6 +/- 1.5 % injected dose (ID)/mL x 10(-3); P < .001). A concentration value of 8.3 %ID/mL x 10(-3) was found to best separate lymphoma and benign uptake, with a sensitivity of 90%, a specificity of 93%, a positive predictive value of 84%, and a negative predictive value of 96%. CONCLUSION Lymphoma and benign hilar uptake differ significantly in their concentration of Ga 67. The present study shows that quantitative Ga-67 SPECT reliably differentiates lymphoma and benign uptake.

Malignant Lymphoma in First‐Degree Blood Relatives

The statistical significance of familial lymphoma in first‐degree blood relatives was evaluated for the series of all lymphoma cases referred to our department since 1968. Four pairs of immediate relatives with Hodgkins disease (HD) were found among 183 patients diagnosed between 1960 and 1980. The expected number during that period was 0.45. Thus, close relatives of HD patients had about ninefold increased risk of the disease (P < 0.005). Mixed‐cellularity was the most common subtype in these familial cases (6/8 patients). There were three pairs of close relatives with non‐Hodgkins lymphoma (NHL) among 532 patients diagnosed during the same period, 1960–1980. The expected number was 3.86. These findings further indicate that HD may differ from NHL with regard to familial clustering.

Utility of gallium-67 scintigraphy in low-grade non-Hodgkin's lymphoma.

PURPOSE Low-grade non-Hodgkins lymphoma (LGNHL) has traditionally been considered non-gallium-avid. The sensitivity of gallium 67 (67Ga) scintigraphy when using modern equipment and techniques in patients with LGNHL was investigated. MATERIALS AND METHODS Fifty-seven consecutive patients with LGNHL underwent 67Ga scintigraphy at initial presentation (n = 40), when tumor progression occurred during treatment (n = 3), and at suspected disease recurrence after continuous clinical remission (CCR) (n = 14). Planar and tomographic images were obtained with either a very large field-of-view or a dual-head digital camera. Of 45 patients with Ga-avid LGNHL, 30 underwent 93 follow-up scans (one to six studies per patient). Scan findings were correlated with clinical and computed tomographic (CT) findings and with patient outcomes. RESULTS 67Ga scintigraphy was positive in 45 of 57 patients (sensitivity, 79%) and in 113 of 164 disease sites (sensitivity, 69%). The sensitivity was higher in the more common types of LGNHL: follicular, predominantly small cleaved cell (FSC), and follicular, mixed small cleaved and large cell (FM) (84% and 91% in patients and 72% and 71% in disease sites, respectively). Sensitivity was lower in patients with mucosa-associated lymphoid tissue lymphoma (MALT) and small lymphocytic lymphoma (SL). Among 28 patients with disease recurrence after CCR (14 with and 14 without baseline studies), 67Ga scan was positive in 25, for a sensitivity of 89% for detection of disease recurrence. CONCLUSION When modern technology is used, 67Ga scintigraphy has good sensitivity in patients with LGNHL. It therefore can be used to monitor response to therapy and to provide early detection of disease recurrence in these patients.

The incidence of lymphoma in first-degree relatives of patients with Hodgkin disease and non-Hodgkin lymphoma

The precise incidence of familial Hodgkin disease (HD) and non‐Hodgkin lymphoma (NHL) in first‐degree relatives is unknown. Through record linkage using two population‐based sources, the authors estimated the risk of HD and NHL in family members of lymphoma probands.