JOURNAL OF CANCER RESEARCH AND ONCOBIOLOGY (ISSN:2517-7370)

Background: Many studies suggested that lactate dehydrogenase (LDH) is elevated in most neoplasms, including Hodgkin’s lymphoma. LDH is not specific to diagnose the type of cancer, it may provide important information toHodgkin’s lymphoma patients including: clinical and biological characteristics, risk stratification according IPS, response to treatment, disease relapse, disease progression and predicting outcome.

Aim of study: Studying the correlation between pre – treatment serum LDH and the clinical, laboratory, and histological characteristics of Hodgkin lymphoma patients in our center in Syria

Patients and Methods: This was retrospective study conducted from a Single Institution at University Tishreen hospital in Lattakia city, Syria, over a period of five years from January 2011 to December 2015. 208 patients (85 female, 123 male) were enrolled in the study. Inclusion criteria were newly diagnosed patients of Hodgkin lymphoma aged more than 14 years, who were admitted to our center of chemotherapy. We analyzed recorded data from patient’s files. Patients or their guardians provided written informed consent to participate in the study. The sample is divided into two groups according to pre-treatment Serum LDH: LDH > 480 (65 pts. ) and LDH ≤ 480 (143 pts. ). Then we have assessed the correlation between pre – treatment serum LDH and the clinical, laboratory, and histological characteristics of Hodgkin lymphoma patients.

Results: The study sample included 208 cases of newly diagnosed Hodgkin lymphoma. According to the criteria for entering the study (123 males, 59. 10% and 85 females, 40. 90%). The ages of the study sample patients ranged from 14 to 79 years, with the average age of the study sample 31. 5 years. The sample was distributed according to the histological type: Nodular sclerosis 65. 4%, Mixed cellularity 31. 3%, Lymphocyte-Rich 2. 4%, Lymphocytic depletion 1%. The sample was distributed according to staging: Stage I (5. 8%), Stage II (44. 2%), Stage III (33. 2%), and Stage IV (16. 8%). Advance stage (86. 5%) and Limited (13, 5%). General symptoms B were seen in 82. 7% of patients. The Mediastinal mass was found in 46. 7% of the research sample and Bulky was greater than 10 cm in 10. 6% of the study patients. Our study revealed that there are no statistically significant differences according to sex and age between the two groups of Hodgkin’s lymphoma patients, as well as the histological type. The group LDH > 480 was associated with a higher elevation in WBC, AMC, and more lower in HGB and ALB. There are statistically significant differences between the two groups of Hodgkin’s lymphoma patients according to the presence of B symptoms, Mediastinal mass and its size, staging and spread disease. 

Conclusion: Pre- treatment serum LDH more than 480 u/ml is an important indicator of the severity and prognosis of Hodgkin lymphoma. It is highly clinically associated with advanced stage, presence of B symptoms, bulky mediational mass.

Hodgkin lymphoma, Pre - treatment serum LDH, patient’s characteristics.

LDH: Lactate dehydrogenase
HL: Hodgkin’s lymphoma
NHL: Non -Hodgkin’s lymphoma
WHO: World Health Organization
NLPHL: Nodular lymphocytic predominant Hodgkin’s lymphoma
NSHL: Nodular sclerosing Hodgkin’s lymphoma
LRHL: Lymphocyte-rich HL Hodgkin’s lymphoma
MCHL: Mixed cellularity Hodgkin’s lymphoma
LDHL: Lymphocyte depletion Hodgkin’s lymphoma
IPS: International prognostic factors
ESR: Erythrocyte sedimentation rate
WBC: White blood cells count
ANC: Absolute neutrophils count
ALC: Absolute lymphocytes count
AMC: Absolute monocytes count
LMR: Lymphocytes monocytes ratio
HGB: Blood Hemoglobin concentration
PLT: Platelets count
ALB: Serum Albumin

Hodgkin’s lymphoma (HL) is a neoplastic B cell lymphoma begin in lymphoid tissue and spreads to another lymphoid structures and may attack non-lymphoid tissues, it comprises 1% of all cancer patients and 14% of all lymphoma cases. Hodgkin’s lymphoma differ of non -Hodgkin’s lymphoma (NHL) by the presence of Reed-Sternberg cells [1-2]. It is a curable disease, Cure rates approach 80-90% of patients, and HL have the best outcome among hematological malignancies and neoplastic diseases [3]. According to World Health Organization(WHO), Hodgkin’s lymphoma is classified into two distinct entities: nodular lymphocytic predominant HL(NLPHL), and classical HL. Classical HL comprises 95% of all HL patients, and can be histologicment classified into four different subtypes; nodular sclerosing HL (NSHL), which is the most common histological subtype, lymphocyte-rich HL (LRHL), mixed cellularity HL (MCHL) and lymphocyte depletion HL (LDHL) [4-5]. The “International Prognostic Factors Project on Advanced Hodgkin’s Disease” suggested seven parameters had prognostic significance in Hodgkin lymphoma patients. These were age, sex, stage IV disease, low albumin level ( < 4. 0 g/dL), anemia ( < 10. 5 g/dL), leukocytosis ( > 15000/mm3) and lymphopenia ( < 600/mm3). The risk stratification of HL depend on a number of prognostic factors for determining early- and advanced-stage HL, theses prognostic were bulky disease, erythrocyte sedimentation rate (ESR), LDH, hemoglobin, serum albumin levels, presence of “B” symptoms, age and extra lymphatic involvement [6]. Lactate dehydrogenase (LDH) is a cytoplasmic enzyme, which is widely expressed in many tissues such as heart, muscle, and various tumors, and it is detectable in serum. It catalyzes the reduction of pyruvate to form lactate, which is the last step of glycolysis. In malignancies, cancer cells metabolism is shifted to aerobic glycolysis and pyruvate transformation to lactate is unregulated. Lactate dehydrogenase (LDH) is often raised in aggressive cancer and hematological malignancies. The tumor microenvironment acidification can leading to tumor progression and metastasis. High serum lactate dehydrogenase levels have been reported as a poor prognostic indicator in many solid tumors such as non- small cell lung cancer, malignant lymphoma, pancreatic carcinoma, and colorectal cancer. It is also correlates with staging, poor outcome and metastasis in many solid tumors [7]. Many studies suggested that lactate dehydrogenase (LDH) is in most neoplasms, including Hodgkin lymphoma. LDH is not specific to diagnose the type of cancer, it may provide important information to risk stratification according IPS, response to treatment, disease relapse, disease progression and predicting outcome [8]. Many previous studies show significant correlation between serum LDH levels and staging of lymphoma. Really, increased serum LDH is a common finding in patients with cancer and is highly correlated to tumor aggressiveness or a high tumor burden [9-10]. Some studies suggest that Lactate Dehydrogenase (LDH) levels reflect the total amount of tumor cells. it represent a valuable biochemical parameter in patients with lymphomas and its serum level has been considered as very important in the evaluation of disease spread in both Hodgkin and non -Hodgkin lymphomas. It might be used as indicator to determine Hodgkin’s disease severity and prognosis in addition to other prognostic factors [11-16]. Other studies suggest that high levels of LDH were significantly higher among patients with B symptoms, bulky disease, extra nodal involvement, low hemoglobin concentration and low serum albumin levels among Hodgkin lymphoma patients [17] which prompted us to study the correlation between pre – treatment serum LDH and the clinical, laboratory, and histological characteristics of Hodgkin lymphoma patients in our center?

Patients and Methods: This was retrospective study conducted from a Single Institution at University Tishreen hospital in Lattakia city, Syria, over a period of five years from 1 January 2011 to 31 December 2015. 208 patients (85 female, 123 male) were enrolled in the study. Inclusion criteria were newly diagnosed patients of Hodgkin lymphoma aged more than 14 years, who were admitted to our center of chemotherapy. We analyzed recorded data from patient’s files: medical history, full physical examination complete blood count, AMC, ALC, LMR, erythrocyte sedimentation rate, liver function tests, serum LDH, serum Albumin. , histological type, radiological investigations, bone marrow biopsy, staging, spread of disease, Mediastinal bulky mass and international prognostic factors IPS. Patients or their guardians provided written informed consent to participate in the study. The sample is divided into two groups according to pre-treatment Serum LDH: LDH > 480 (65 pts. ) and LDH ≤ 480 (143 pts. ). Then we have assessed the correlation between pre – treatment serum LDH and the clinical, laboratory, and histological characteristics of Hodgkin lymphoma patients. We used frequencies and percentages for qualitative variables, and measures of central tendency for quantitative variables. The initial variables were tested using the log-rank test, and groups were compared by using the log-rank test. Results were statistically significant when p-value ˂0. 05. The program (IBM SPSS statistics) version19 was adopted to calculate statistical transactions and analyze results.

Results: The study sample included 208 cases of newly diagnosed Hodgkin lymphoma. According to the criteria for entering the study Criteria at the Radiation Chemotherapy Center at Tishreen University Hospital during the period between 1-1- 2011 until 31 December 2015, (123 males, 59. 10% and 85 females, 40. 90%) of patients with Hodgkin’s lymphoma. The ages of the study sample patients ranged from 14 to 79 years, with the average age of the study sample 31. 5 years. The sample was distributed according to the histological type: Nodular sclerosis 65. 4%, Mixed cellularity 31. 3%, Lymphocyte-Rich 2. 4%, Lymphocytic depletion 1%. The sample was distributed according to staging: Stage I (5. 8%), Stage II (44. 2%), Stage III (33. 2%), Stage IV (16. 8%). Advance stage (86. 5%) and Limited (13, 5%). General symptoms B were seen in 82. 7% of patients. The Mediastinal mass was found in 46. 7% of the research sample and Bulky was greater than 10 cm in 10. 6% of the study patients. We note that the combined chemotherapy with radiotherapy represented 43. 7% of the research sample studied against 56. 3% for chemotherapy alone. The sample was distributed according to pre-treatment serum LDH as fowling: LDH > 480 in 31, 25% (65/208pts), LDH ≤ 480 in 68, 75% (143/208pts). The Distribution of sample of patients with Hodgkin lymphoma according to risk factors for IPS is shown in [Table 1]. 

We have studied the correlation between pre-treatment Serum LDH and demographic variables, histological type in Hodgkin lymphoma patients. Our study revealed that there are no statistically significant differences according to sex and age between the two groups of Hodgkin’s lymphoma patients, as well as the histological type, (p > 0, 05) as shown in [Table 2]. 

We have also studied the influence of pre-treatment Serum LDH on Laboratory findings as white blood cells count (WBC), absolute neutrophils count (ANC ), absolute lymphocytes count (ALC), absolute monocytes count (AMC), lymphocytes monocytes ratio (LMR ), blood Hemoglobin concentration (HGB), Platelets count (PLT) and serum Albumin (ALB). Our study conducted that there are statistically significant differences between the two groups of Hodgkin’s lymphoma patientsfor all laboratory parameters, except for platelet counts (PLT), ANC and ALC. The group LDH > 480 was associated with a higher elevation in WBC (12910. 7±5969. 5 /ml versus 10894. 4±5162. 8 /ml, P-value 0, 01) , AMC (537. 1±406. 8/ml versus 419. 7±366. 5/ml, P-value 0, 04), and more lower in HGB (10. 7±1. 7g/dl versus 11. 3±1. 9g/ dl, P-value 0, 02), LMR (5. 5±5. 7 versus 8. 5±10. 4, P-value0, 02) and ALB (3. 5±0. 7g/versus 3. 7±0. 7g/dl, P-value 0, 04) as shown in [Table 3].

Finally, we have studied the correlation ship between baseline Serum LDH and clinical characteristics (the presence of B symptoms, the presence of Mediastinal mass, bulky disease, staging and disease spread) in Hodgkin’s lymphoma patients. We found that there are statistically significant differences between the two groups of Hodgkin’s lymphoma patients according to the presence of B symptoms, Mediastinal mass and its size, staging and spread disease. B symptoms were observed in (93. 8%) of the LDH group > 480 versus (77. 6%) of LDH group ≤ 480, (p < 0. 004). the Mediastinal mass and its size was observed in(61. 5%) of the LDH group > 480 versus (39. 9%)of LDH group ≤ 480, ( p < 0. 006). may, the important significant difference between the two groups of Hodgkin’s lymphoma patients was the staging of disease and its spread, stage (III. IV) was observed in (73. 9%) of the LDH group > 480 versus (39. 2%) of LDH group ≤ 480, ( p < 0. 0001), advance disease was observed in (96. 9% of the LDH group > 480 versus (81. 8%) of LDH group ≤ 480, ( p < 0. 003) as shown in [Table 4].

Discussion: The study sample included 208 cases(123 males, 59. 10% and 85 females, 40. 90%), average age of the study  sample 31. 5 years, the sample was distributed according to the histological type: Nodular sclerosis 65. 4%, Mixed cellularity 31. 3%, Lymphocyte-Rich 2. 4%, Lymphocytic depletion 1%. The sample was distributed according to staging: Stage I (5. 8%), Stage II (44. 2%), Stage III (33. 2%), Stage IV (16. 8%). Advance stage (86. 5%) and Limited (13, 5%). General symptoms B were seen in 82. 7% of patients. The Mediastinal mass was found in 46. 7% of the research sample and Bulky was greater than 10 cm in 10. 6% of the study patients. The sample was distributed according to pretreatment serum LDH as fowling: LDH > 480 in 31, 25% (65/208pts), LDH ≤ 480 in 68, 75% (143/208pts).

Our finding revealed that there are no statistically significant differences according to histological type between the two groups of Hodgkin’s lymphoma patients, (p > 0, 05). we reported also the important significant difference between the two groups of Hodgkin’s lymphoma patients was the staging of disease and its spread, stage (III. IV) was observed in (73. 9%) of the LDH group > 480 versus (39. 2%) of LDH group ≤ 480, ( p < 0. 0001), advance disease was observed in (96. 9% of the LDH group > 480 versus (81. 8%) of LDH group ≤ 480, ( p < 0. 003). This agrees with results of Rawand P et al. [18] who had studied the relationship between Serum Lactate dehydrogenase (LDH) and Presentation, Stage and Histologic type of 13 patients with Hodgkin’s lymphoma (HL) and 37 patients with non-Hodgkin’s lymphoma (NHL) from April to October 2009. They reported that There was no relationship between mean LDH level and histological subtype among HL patients, While in NHL, the mean LDH level among high-grade NHL patients was somewhat higher than that of patients with intermediate grade NHL without statistical significant level (P = 0. 082). They revealed a correlation between the extent of disease represented by stage of lymphoma and Serum Lactate dehydrogenase [18]. Tahannejad Z et al. [19] observed a similar findings in their study from 30 patients who suffered from Hodgkin’s Lymphoma, they revealed that Stages III and IV (advanced stages) were observed in 61. 4% of sample. serum Lactate dehydrogenase was statistically higher in patients in comparison with controls (P < 0. 01). they revealed also elevated levels of Lactate dehydrogenase (LDH) among patients in advanced stages (stages III, IV in comparison patients in early stage initial (stages I, II). (P < 0. 001)(19). In contract, Lucia Nogova et al. [20] suggested that increased serum LDH is most commonly in classical Hodgkin lymphoma, they found an elevated lactate dehydrogenase level in 84% of classical Hodgkin lymphoma patients versus 68% in lymphocyte predominance Hodgkin lymphoma patients (LPHL) [20]. Our study revealed that there was an important correlation between the presence of bulky Mediastinal mass and pre-treatment serum LDH, it was observed in(61. 5%)of the LDH group > 480 versus (39. 9%)of LDH group ≤ 480, ( p < 0. 006), this is explained by Straus DJ et al. [21], they reported that elevated serum LDH reflect the total amount of tumor cells in the mediastinum representing as Bulky Mediastinal mass in Hodgkin lymphoma patients [21]. Our study suggested that there are statistically significant differences between the two groups of Hodgkin’s lymphoma patients according to the presence of B symptoms, Mediastinal mass and its size, staging and spread disease. B symptoms were observed in (93. 8%) of the LDH group > 480 versus (77. 6%) of LDH group ≤ 480, (p < 0. 004). There were statistically significant differences between the two groups of Hodgkin’s lymphoma patients for laboratory parameters as hemoglobin concentration and serum albumin, The group LDH > 480 was associated with a more lower levels in HGB (10. 7±1. 7g/ dl versus 11. 3±1. 9g/dl, P-value 0, 02), and ALB (3. 5±0. 7g/versus 3. 7±0. 7g/dl, P-value 0, 04). this agrees with Saadettin Kılıckap et al. [17]. They analyzed data of 391 HL patients (61% male, 39% female; mean age 35. 7±15. 1 years). The most common classical HL histological subtype was nodular sclerosing HL (NSHL) (42. 7%). The most common stage was II 50. 4%. Pretreatment serum LDH were higher among patients with “B” symptoms, bulky disease extra nodal involvement, low hemoglobin concentration and low serum albumin [17]. Our finding agrees also with E. Bien et al. [8] They studied prospectively the utility of serum Lactate dehydrogenase (LDH) and other markers in diagnosis, prognosis and monitoring of response to therapy in 30 Childs presenting Hodgkin’s lymphoma(HL). They revealed that increased pretreatment serum LDH is correlated with bulky disease and with advanced HL stages. Pretreatment serum LDH was found elevated in 90% of patients with bulky disease and elevated in 71% of children with advanced stages Pretreatment Serum LDH may act as markers for diagnosis and used in monitoring of therapy efficacy in childhood HL [8]. B-symptoms are caused by the production of pro-inflammatory cytokines by the Hodgkin tumor cells and associated with other laboratory abnormalities such as elevated serum LDH. Anemia is characterized by alterations in iron metabolism. Elevated production of hepcidin, which inhibits the absorption of iron from the intestine, and iron, stores in the reticuloendothelial system especially the liver, that result in hyperferritinemia. Elevated serum ferritin have been recognized in HL and have been suggested to be a prognostic marker ago. Low levels of serum albumin are associated with a bad prognosis in many neoplasias, including HL. The IPS score defines albumin levels of 4. 0 g/dl as cut-point. Serum albumin is reduced by increased production of inflammatory cytokines such as Interleukin -6, witch inhibit its hepaticsyntheses [4]. Common findings in WBC counts in HD patients include leukocytosis with neutrophilia, lymphocytopenia, and monocytosis. In the IPS, the prognostic cut point for white blood cell count is 15000/microL, for lymphocytopenia it is 600/microL [22-23]. Recently, the monocyte count, monocyte count /the lymphocyte count ratio (LMR) has been reported to be an important prognostic factor in HL. Since its publication in 2016, The prognostic value of LMR is controversial, lower LMR at diagnosis was associated with poor OS and PFS in HL, and LMR cut-off values ranged from 1. 1 to 2. 8 [24-25]. The optimal cut-off of LMR for the elderly patients HD was 2. 2. In the non‐elderly patients ( < 60 years), patients with LMR < 2. 8 had significantly lower OS compared with those with LMR ≥2. 8 (p  <  0. 001, both) [26]. This present study approved that there are statistically significant differences between the two groups of Hodgkin’s lymphoma patients for all white blood cells (WBC) parameters, except for ANC and ALC. The group LDH > 480 was associated with a higher elevation in WBC (12910. 7±5969. 5 /ml versus 10894. 4±5162. 8 /ml, (P-value 0, 01) , higher AMC (537. 1±406. 8/ml versus 419. 7±366. 5/ml, (P-value 0, 04), and lower in LMR (5. 5±5. 7 versus 8. 5±10. 4, (P-value0, 02). This study agrees with Theodoros P eft al. [27]. They revealed that lower LMR was strongly associated with many prognostic factors reflecting tumor burden and biological aggressiveness of the disease, including B-symptoms, advanced stage, number of involved sites, anemia, leukocytosis, lymphocytopenia, thrombocytosis, elevated ESR (≥50 mm/hour), albumin < 4 g/dL, elevated lactate dehydrogenase (LDH), and high IPS (≥3) [27].

Pre- treatment serum LDH more than 480 u/ml is an important indicator of the severity of Hodgkin lymphoma. It is highly clinically associated with advanced stage, presence of B symptoms, bulky mediational mass. It is also associated with a higher elevation in WBC, AMC, and more lower in HGB, LMR and serum ALB. Our study revealed an important correlation between high levels of pre - treatment serum LDH and bad international prognostic factors (IPS) of Hodgkin lymphoma. Therefore, Further and future studies are suggested for more evaluation its actual role in predicting the outcome of Hodgkin lymphoma patients. 

Ethics approval and consent to participate

Written consent was obtained for the patients to participate in the study, written informed consent was obtained from a parent for participants under 18 years old. Our institutional ethics committee in the faculty of medicine- Tishreen University approved our study.

Consent for publication: written consent to publish this information was obtained from study participants.
Availability of data and materials: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

No conflict of interest. 

Funding was received. 

Corresponding author analyzed and interpreted the patient data. 

Not applicable

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