Obesity and Metabolic Syndrome among Adult Lymphoma Survivors

Research Article

Ann Hematol Oncol. 2019; 6(10): 1275.

Obesity and Metabolic Syndrome among Adult Lymphoma Survivors

Daniele A*, De Summa S, Lerario G, Divella R, Ditonno P, Ciavarella S, Paradiso AV, Sciacovelli AM, De Luca R, Savino E, and Guarini A*, Minoia C*

National Cancer Institute, IRCCS Istituto Tumori “Giovanni Paolo II” Bari, Italy

*These Authors contributed equally as last authors in this study

*Corresponding author: Antonella Daniele, National Cancer Institute, IRCCS Istituto Tumori “Giovanni Paolo II” Bari, Italy Viale Orazio Flacco 65, 70124 Bari, Italy

Received: October 13, 2019; Accepted: November 26, 2019; Published: December 03, 2019


Background: Metabolic dysfunction, including the metabolic syndrome (MetSyn) and insuline resistance, is a long-term complication of curative treatment for many cancer patients including lymphoma survivors. In these patients, prognosis and quality of life can be adversely influenced by obesity, physical inactivity and metabolic dysfunction so, preventive measures, including dietary counseling and tailored exercise should be initiated early in the course of survivorship.

Patients and Methods: The study was conducted analyzing, in relation to the diagnosis of Diffuse Large B-cell Lymphoma (DLBCL), Hodgkin Lymphoma (HL) and therapy, the presence of MetSyn, obesity, sarcopenia, and type IIA and IIB dyslipidemia. We prospectivelly enrolled 111 lymphoma survivors aged between 24 and 82 years in continuous remission of lymphoma for at least 3 years within the “CCM2014” project supported by the Italian Ministry of Health. Each of them underwent an anthropometric and plicometric evaluation and measurement of metabolic and inflammation parameters (glycaemia, total cholesterol and HDL, triglycerides, C-reactive protein and β-2 microglobulin).

Results: Our results showed a lower risk of developing MetSyn in HL patients than in DLBCL (p‹0.001), while steroid use during therapy significantly increased the risk of MetSyn and sarcopenia in DLBCL patients. Concerning the dyslipidemia IIa, multivariate analysis showed that the HL group had asignificantly lower risk than DLBCL of developing these conditions. Dyslipidemia IIb showed instead of being related to smoking. Particularly, in the univariate analysis both ex-smokers and smokers have a significantly higher risk of developing this metabolic disorder. Anova test, showed in the DLBCL group a statistically significant correlation concerning the waist circumference in both women and men with MetSyn no MetSyn with p›0.05 and p=0.005 respectively; statistically significant association was also observed in the percentage of lean mass; DLBCL men in the group with MetSyn had a significant sarcopenia compared to those without MetSyn (p = 0.04).

Conclusion: These data suggest that DLBCL patients have a higher risk of developing MetSyn and sarcopenia compared to HL, most likely as a result of taking steroids, so an early nutritional intervention associated with adequate physical activity could reduce the risk of onset of both complications in lymphoma survivors. These conclusions had never been previously reported in an Italian or European population of lymphoma survivors, remarking that, also in Countries in which the Mediterranean diet is diffused, these kinds of complications could occur.

Keywords: Metabolic syndrome; Obesity; Lymphoma survivors


Malignant lymphomas represent the fifth type of cancer by frequency in the Western World, with an incidence of about 19-20 cases per 100,000 inhabitants per year [1]. The incidence of lymphomas is largely influenced by geographical, racial and temporal factors and is higher in industrialized countries, in male and white race. Survival rates for lymphoma have gradually increase; age-adjusted 5-year survival for HL in adults is about 81% and for Non-Hodgkin’s Lymphomas (NHL) about 60% [2,3]. With increasing numbers of cancer survivors, attention has been drawn to long-term complications of curative cancer treatment, including a range of metabolic disorders. Treatment relatedobesity and metabolic syndrome in adult survivors to lymphoma are risk factor for cardiovascular disease. Both conditions often begin during therapy. The Term Metabolic Syndrome (MetSyn), previously known as syndrome X, defines a cluster of physiological, biochemical and metabolic factors that directly increase the risk of developing atherosclerotic cardiovascular disease, diabetes mellitus and all causes of mortality [4]. Among the various diagnostic criteria proposed, the most widely accepted are those established by the National Cholesterol Education Program Adult Treatment Panel III [5]. The prevalence of the MetSyn increases with age and varies based on genetic factors. Increasing evidence shows that the MetSyn and its components such as obesity and insulin resistance are associated with cancer and treatment [6-8]. Obesity is one of the biggest public health problems on the level worldwide, as it concerns both the populations of the industrialized countries and those of the developing countries. It is estimated that at least 250 million people worldwide are currently suffering from obesity. It is a chronic disease with multifactorial pathogenesis, characterized by an excessive accumulation of body fat, with a consequent increase in weight, resulting from the interaction between predisposing genetic factors and favorable environmental factors [9]; the latter are mainly represented by a sedentary lifestyle, a diet rich in fats and simple sugars, on the whole, by an imbalance between income and energy expenditure. Excessive amounts of free fatty acid lead to insulin resistance and glucose intolerance, and the adipose tissue is the main source of variety of proinflammatory cytokines that may contribute to the development of cardiovascular changes. The increased adipose tissue, which today is considered a true endocrine/autocrine organ, is responsible for an abnormal secretion of free fatty acids and peptides involved in various regulatory functions, which contribute to the development of typical complications of overweight, such as cardiovascular diseases, type 2 diabetes mellitus, hyperlipidemia and hepatic steatosis and Nonalcoholic Fatty Liver Disease (NAFLD) [10].

Insulin resistance is the condition in which insulin-mediated glucose uptake is impaired and this is considered to be the primary event in the development of these metabolic disturbances; it is present in patients with non-insulin dependent diabetes mellitus or impaired glucose tolerance, but can also be found in individuals with normal glucose tolerance. The recent proposed criteria for MetSyn suggest the role of obesity and visceral adipose tissues are associated to insulin resistance [11].

Although the same aetiologic factors as for the general population can be assumed to play a role in the development of the metabolic syndrome in cancer survivors, other explanations can be suggested in the development of this syndrome in these patients. Disturbances of the hypothalamic-pituitary axis and their target organs, like deficiencies of growth hormone and gonadal hormones, have been linked to the development of the metabolic syndrome [12-16]. Some forms of cancer treatment can have harmful effects on the functioning of the hypothalamic-pituitaryaxis and the endocrine organs [17,18]. Therefore, it is conceivable that the occurrence of endocrine disorders after curative cancer treatment is important for the development of the metabolic syndrome in these long-term cancer survivors. Local treatments (surgery and radiotherapy) and systemic cancer therapy (chemo and hormone therapy) can cause changes in endocrine and metabolic functions that might contribute to the development of the metabolic syndrome.

Several authors have demonstrated a role of Growth Hormone (GH) in metabolic syndrome onset as GH stimulates proteinsynthesis and contributes to lipolysis and it indirectly exerts insulinlike effects, such as stimulation of glucose uptake into peripheral tissue, via stimulation of IGF-1 production by the liver; decreased levels of this factor is associated with change in body composition, such as reduction in lean body mass and increase in fat mass which are associated with dyslipidaemia and insulin resistance [19].

A relevant question is whether the MetSyn is more prevalent in cancer survivors after cancer treatment respect to healthy population and, in fact, different authors have evaluated this aspect.

In 1996, Talvensaari et al. described a role of GH with combination of obesity, hyperinsulinaemia and reduced high-density lipoprotein (HDL) cholesterol, in a group of long term survivors of childhood cancer who were mainly given a combination of chemotherapy and radiotherapy reportingan increased risk of the metabolic syndrome in survivors respect to healthy control. Growth-hormone deficiency is the common endocrine dysfunction in survivors treated with radiotherapy and is associated with obesity [20].

MetSyn seems to be an emergent complication of NHL survivors, as shown in a meta-analysis performed in 2012, and of patients who had undergone a hematopoietic stem cell transplant (autologous or allogeneic) [21,22]. In the subset of lymphoma survivors, Body Mass Index (BMI) has been more frequently analyzed, due to its easier evaluation. In different series, both HL and NHL survivors present an increased BMI in comparison to the general population [23,24], but this parameter cannot be considered as a surrogate for MeSyn.

The aim of this study was to assess in a prospective study the prevalence MeSyn in lymphoma survivors in order to offer an early and adequate nutritional support to reduce the risk of secondary neoplasms, metabolic disorders and cardiovascular late events.

Patients and Methods

This is a monocentric study conducted from November 2016 to July 2018; we enrolled 111 consecutive patients (62 women and 49 men), median age 51 years (range, 22-82) in continuous remission of both NHL and HL, for at least 4 years and in current follow-up at our Institution as part of the “Centre for Disease Control Program 2014 CCM2014) launched by the Italian Ministry of Health. The study was approved by the local Ethical Commettee and patients willing to participate signed informed consent. Clinical data related to the primary onco-haematological disease and anti-neoplastic treatment were obtained by electronic database. In the context of an onco-haematological follow-up visit, each patient was subjected to nutritional evaluation of the bi-compartment by anthropometry and plicometry and a questionnaire was administered to each of them to assess lifestyles (physical activity, smoking, use of alcohol, adherence to specific food models such as Mediterranean, Vegan Vegetarian, etc.) [25], pharmacological therapies in progress, pathological states of nutritional interest, food allergies or intolerances, daily food intake and/or eating behavior disorders, possible dependence on opioids, tranquilizers or sedatives and sleep disorders.

Anthropometry and Plicometry measurement

Weith and heith of all patients were measured with diagnostic device (Millennium 3 DAVI & CIA – Barcelona, Spain).

At the same time, the right and left circumferences (cm) of the wrist, forearm and arm, shoulders, thorax, waist, abdomen, hips, median of the thigh and median of the calf were measured (professional meter BMI, GIMA, Gessate (MI)- Italy) according the standard techniques described by Lohman [26]. The World Health Organization (WHO) definitions of obesity (body mass index, BMI›30 kg/m2 and overweight (BMI 25-29.9kg/m2) were used [27]. The percentage of Fat Mass (FT) and Lean Mass (LM) was carried out using a FAT-1 plicometer (GIMA- Italy) which measures the thickness of skin folds in various districts and assesses the nutritional status of the subject under examination and the sectoral distribution of its adipose tissue. The Durnin-Womerslay measurement of 7 folds (bicipital, tricipital, axillary, subscapular, abdominal, over-iliac and median thigh) was performed [28]. The Basal Energy Expenditure (BEE) has been calculated according to the Harris & Benedict Equation (HBE): for male gender: 66.47 + (13.75 x weight in kg) + (5.003 x height in cm) - (6.775 x age in years). For female gender, the following equation was utilized: 655.09 + (9.563 x weight in kg) + (1.85 x height in cm) - (4.676 x age in years) [29]. The ideal weight of each patient was calculated using the Lorenz formula which includes the following calculation: for male gender: (height in cm -100) – (height in cm -150) /4. For female gender: (height in cm -100) – (height in cm -150) /2.

Blood samples assay

Following overnight fasting, blood samples for measurement of triglyceridae, glycaemia, HDL- cholesterol, total cholesterol, β-2 microglobulin, albumin, C-reactive protein were collected after overnight fasting using COBAS c311/501 (Roche-Diagnostic Limited S.p.A Basel- Switzerland); Definition of the MetSyn was done according to the National Cholesterol Education program Adult treatment Panel III guidelines defined as at least three of the following parameter: [4] waist circumference›102 cm in men and ›88 in women, blood pressure ›130/85 mm/Hg, hypertrigly ceridaemia, hyperglycaemia and lower HDL-cholesterol. The classification of dyslipidemia was performed according to Fredrickson’s phenotypes accepting from World Health Organization (WHO).

Statistical analysis

Data were analyzed by using statistical analysis and size power analysis and graphic (NCSS-PASS) 2007 software. The serum levels of anthropometric and metabolic parameters are expressed as mean±standard deviation.

The correlation between the serum levels of metabolic parameter in two groups (NHL and HL) of patients was performed by t-test while the correlations with anthropometric parameters were performed by Analysis Of Variance (ANOVA). A p value of less than 0.05 was considered as statistically significant.

Univariate and mutivariate logistic regression were performed through generalized linear model, using binomial family and logit link. The “MASS” R package was used in the studio Version 1.1.447 [25]. Results are reported as hazard ratio and 95% confidence interval and they were considered significant when p-value ‹ 0.05.


In this study we enrolled 57 NHL of whom 42 Diffuse Large B-cell lymphoma, 1 Burkitt lymphoma, 1 Primary Central nervous system lymphoma, 1 Mantle cell lymphoma, 7 Follicular lymphoma, 2 Small lymphocytic lymphoma, 2 Marginal zone lymphoma, 1 Anaplastic large cell lymphoma CD30+ ALK+ and 55 classical HL (31 women and 24 men) in current follow-up at our Institute, with a median of 8 years since remission of the disease (range: 4-48). NHL patients had been treated in the majority of cases with CHOP (cyclophosphamide, vincristinem doxorubicin, prednisone) or CHOP-like regimes which included high-dose steroids. HL patients had been treated with ABVD (doxorubicin, bleomicin, vinblastine, dacarbazine) with or without radiotherapy. The 14.9% (n. 17) received a second line chemotherapy, which for 5.2% (n.6) was followed by a autologous stem cell transplant. The baseline clinical-anthropometric and lifestyle habits of 111 lymphoma patients are shown in (Table 1). The correlation between the mean of the anthropometric-plicometric values and the metabolic parameters expressed in mean ± SD was carried out used the analysis of variance (ANOVA) considering significant p-value ‹of 0.05.