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Year : 2020  |  Volume : 45  |  Issue : 3  |  Page : 148-155

Characteristics of extranodal classic Hodgkin lymphoma: a retrospective analysis of 175 patients

1 Clinical Hematology Unit, Internal Medicine Department, Oncology Center, Mansoura University, Egypt
2 Medical Oncology Unit, Internal Medicine Department, Oncology Center, Mansoura University, Egypt
3 Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission01-Feb-2020
Date of Acceptance16-Apr-2020
Date of Web Publication23-Jun-2021

Correspondence Address:
Shaimaa El-Ashwah
Lecturer of Clinical Hematology Unit, Internal Medicine Department, Oncology Center, Mansoura University, Mansoura, 35516
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejh.ejh_9_20

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Aim To find out the characteristics of extranodal classical Hodgkin lymphoma (cHL).
Patients and methods A retrospective analysis was done on 175 patients with cHL who attended the Oncology Center of Mansoura University from January 1, 2008 to May 31, 2016, with a median follow-up of 2.93 years (range, 0.05–10.2 years).
Results One (0.6%) patient was diagnosed with primary extranodal cHL and 48 (27.4%) patients had secondary extranodal cHL. Liver (25.3%), lung (24.1%), and the bone (20.3%) were the most frequent extranodal sites. A total of 27 (55.1%) patients had one extranodal site, 16 (32.7%) patients had two extranodal sites, and six (12.2%) patients had more than or equal to three sites. Overall, 42 (85.71%) patients with extranodal sites were less than 45 years old (P=0.019), 15 (30.6%) had splenic involvement (P=0.003), 39 (79.6%) patients had absolute monocyte count /absolute lymphocyte count (monocyte-lymphocytes ratio) more than or equal to 0.305 (P<0.001), 36 (73.47%) patients had International Prognostic Score more than or equal to 3 (P<0.001), 23 (46.9%) patients achieved complete response, and 10 (20.4%) patients achieved partial response. In univariate analysis, extranodal disease was associated with inferior disease-free survival and overall survival (P=0.037 and 0.001, respectively), but it lost its significance using multivariate analysis (P=0.12 and 0.54, respectively).
Conclusion Most of the extranodal cHL cases were secondary (97.96%) and significantly associated with unfavorable clinical features and lower response rate to standard treatment. To our knowledge, this is the first study to demonstrate that extranodal cHL is statistically associated with elevated monocyte-lymphocytes ratio.

Keywords: disease-free survival, extranodal, Hodgkin disease, monocyte-lymphocyte ratio, overall survival

How to cite this article:
El-Ashwah S, Fahmi MW, El-Badrawy A. Characteristics of extranodal classic Hodgkin lymphoma: a retrospective analysis of 175 patients. Egypt J Haematol 2020;45:148-55

How to cite this URL:
El-Ashwah S, Fahmi MW, El-Badrawy A. Characteristics of extranodal classic Hodgkin lymphoma: a retrospective analysis of 175 patients. Egypt J Haematol [serial online] 2020 [cited 2021 Sep 23];45:148-55. Available from: http://www.ehj.eg.net/text.asp?2020/45/3/148/319163

  Introduction Top

Hodgkin lymphoma (HL) is an uncommon malignancy [1]. Most cases are classic HL (up to 95%), and a minority of them are nodular lymphocyte-predominant HL (∼5%) [2]. The spread of HL is highly predicted. At the time of diagnosis, 80% of patients present with asymptomatic contiguous supradiaphragmatic lymphadenopathy. Inguinal lymph nodes involvement is less common [3]. Extranodal infiltration is less seen in HL than in non-Hodgkin’s lymphoma, and skeleton is the commonest extranodal site in HL [4].

Primary extranodal lymphoma (ENL) is defined as a lymphoma that originates in non-nodal sites, whereas secondary ENL usually accompanies nodal infiltration, either it originates in lymph node and spreads to adjacent non-nodal site or spreads hematogenously to extranodal sites. ENL is likely to be more than previously recognized [5]. A large retrospective study found extralymphatic HL is a rare presentation with poor prognosis [6].

Introduction of positron emission tomography/computed tomography (PET/CT) scanning into the staging of HL adds significantly more accurate information to the other standard radiological studies [4], as initial staging is pivotal for detection of extranodal sites and affecting treatment plans [7].

Although the International Prognostic Score (IPS) can predict outcomes in newly diagnosed advanced-stage classical Hodgkin lymphoma (cHL), it is not predictive for limited stage [8].

In this retrospective study, we aimed to evaluate the prevalence and effect of extranodal sites on cHL characteristics and its outcome clinically and through laboratory studies.

  Patients and methods Top

This is a retrospective analysis of 175 patients with cHL admitted at Oncology Center, Mansoura University, from January 1, 2008, to May 31, 2016. A written consent were signed by all patients after approval from the ethical committee. The histopathological diagnosis of cHL was based on WHO classification. The patient characteristics, routine laboratory investigations, radiological staging, treatment, and follow-up data were recorded. All patients were treated with ABVD protocol±IFRT as the standard of care. The response was defined according to the Revised Response Criteria for Malignant Lymphoma [9]. Time to relapse or death was studied. Patients with incomplete recorded data and those diagnosed with NLPHL were excluded from the study. The Institutional Review Board at the Faculty of Medicine, (R.18.10.302 - 2018/10/17), Mansoura University, Egypt, reviewed and approved this study.

Computed tomographic technique

Whole-body and triphasic abdominal CT scanning was performed on 64 multidetector CT scanning system (Brilliance 64; Philips Healthcare, Best, The Netherlands). The precontrast and postcontrast triphasic series were taken by using a 3-mm slice thickness. The postcontrast study was performed using 120 ml of low-osmolar nonionic contrast medium (ioversol, Optiray 350). All images were transferred to the workstation (Extended Brilliance Workspace V3.5.0.2254) for postprocessing. The images were viewed on lung, soft tissue, and bone setting.

Image interpretation

Image interpretation focused on the precontrast attenuation of the lesions, as well as their density phases, number of lesions, vascular invasion, lymph node involvement, and other organs in all postcontrast images. The CT scanning for whole body (all groups of lymph nodes and other organs of the body, as well as bony or pulmonary metastases) was evaluated; moreover, internal architecture, tumor size, organ of origin, and calcifications were evaluated.

Statistical analysis

Data were collected, processed, and analyzed using IBM-SPSS (Statistical Package for Social Scientists) software, version 21.0 (Armonk, NY: USA, IBM Corp.). Categorical data were expressed as count and percent and were compared by χ2 test. Time to an event, for example, death, or relapse, was studied by performing survival analysis and generating a Kaplan–Meier survival plot, and overall survival (OS) and disease-free survival (DFS) were recorded. Multivariate analysis was performed by the Cox proportional hazards model. OS was calculated from the beginning of treatment till death or last follow-up. DFS was calculated from the time of complete response (CR) till time of relapse, death, or last follow-up. Receiver operating characteristic curve of monocyte-lymphocytes ratio (MLR) was conducted for predicting mortality in patients with cHL (area under the curve=0.529, P=0.68 at 95% confidence interval=0.39–0.67). At cutoff value more than or equal to 0.305, sensitivity was 60% and specificity was 56%.

  Results Top

A total of 175 patients with cHL were enrolled in this study; their mean±SD age was 36±15.76 years. The prevalence was higher in females (female/male ratio 119/56). They were categorized as follows: 126 with nodal sites and 49 with extranodal sites.

Extranodal sites

The 49 patients with extranodal disease were one with primary extranodal HL (stage IE) and 48 with secondary extranodal HL (stage IV). The involved extranodal sites were the liver in 20 patients, lungs in 19 patients, bone in 16 patients, malignant effusion in 14 patients, thyroid gland in two patients, paraspinal mass in two patients, intraorbital lesion in one patient, parotid gland in one patient, breast in one patient, stomach in one patient, kidney in one patient, and colon in one patient ([Figure 1]).
Figure 1 Chart for extranodal HL. HL, Hodgkin lymphoma.

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Only one extranodal site was detected in 27 (55.1%) patients ([Figure 2] and [Figure 3]), whereas two extranodal sites in 16 (32.7%) patients ([Figure 4] and [Figure 5]) and more than or equal to three sites in six (12.2%) patients ([Figure 6]).
Figure 2 MDCT scan revealed increased thickness of greater curvature of stomach (arrow). MDCT, multidetector computed tomography.

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Figure 3 MDCT scan revealed multiple submental and bilateral cervical malignant lymphadenopathy (yellow arrows) (a, b) and left thyroid nodule (arrow) (c). MDCT, multidetector computed tomography.

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Figure 4 MDCT scan revealed multiple mediastinal and bilateral axillary malignant lymphadenopathy (yellow arrows) (A), bilateral pleural masses (yellow arrows) (B), right pleural effusion (red arrow) (B), bilateral pelvic malignant lymphadenopathy (yellow arrow), and sclerotic bony lesion of thoracic 11 vertebra (yellow arrow) (D). MDCT, multidetector computed tomography.

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Figure 5 MDCT scan revealed sternal osteolytic bony lesion (arrow) (a), multiple mediastinal malignant lymphadenopathy (arrows) (b), and right parasternal chest wall mass (arrow) (c). MDCT, multidetector computed tomography.

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Figure 6 MDCT scan revealed right pleural effusion (arrow) (a), multiple hepatic and splenic focal lesions (b), cecal mass (yellow arrows) (c), and ascites (yellow arrow) (d). MDCT, multidetector computed tomography.

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Overall, 42 (85.71%) extranodal patients were less than 45 years old, 15 (30.6%) extranodal patients had splenic involvement, 48 (98%) extranodal patients were stage IV, 39 (79.6%) extranodal patients had MLR more than or equal to 0.305, 23 (46.9%) extranodal patients achieved CR, and 10 (20.4%) extranodal patients achieved partial response (PR).

Extranodal disease was strongly associated with age (P=0.019), splenic involvement (P<0.001), advanced stage (P<0.001), IPS more than or equal to 3 (P<0.001), high MLR (P<0.001), and overall response (CR/PR) (P=0.025).

Additionally, there was no statistically significant difference between nodal and extranodal sites according to sex (P=0.4), histopathology (P=0.32), B symptoms (P=0.087), bulky disease (P=0.076), relapse rate (P=0.27), or time to start treatment (P=0.14), as illustrated in [Table 1].
Table 1 Patients’ characteristics

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Variables affecting the overall survival in classical Hodgkin lymphoma

The median OS was not reached after median follow-up of 2.93 years (range, 0.05–10.2 years). Univariate analysis revealed that advanced stage, extranodal sites ([Figure 7]), IPS more than or equal to 3, and high MLR were associated with decreased OS (P≤0.001, P=0.001, P<0.001, and P=0.004, respectively), whereas multivariate analysis revealed that advanced stage and IPS more than or equal to 3 were independently associated with adverse prognosis for survival ([Table 2]).
Figure 7 OS. OS, overall survival.

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Table 2 Overall survival of studied population

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Variables affecting the disease-free survival in classical Hodgkin lymphoma

In cHL cases, extranodal sites and advanced stage were associated with decreased DFS (P=0.037; [Figure 8] and 0.04, respectively). Both lost their significance on multivariate analysis ([Table 3]).
Figure 8 DFS. DFS, disease-free survival.

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Table 3 Disease- free survival of studied population

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  Discussion Top

A known, accurate staging of patients with HL is essential in selecting the treatment modality [10]. Several prognostic factors have been evaluated in cHL to predict outcomes and personalize treatment precisely [11]. For early-stage HL, age more than 50 years, increased erythrocyte sedimentation rate, bulky mediastinal lesion, multiple nodal sites, and extranodal involvement are prognostic factors. For advanced stage, the IPS identified older age, male sex, stage IV, hemoglobin less than 10.5 g/dl, white blood cell count more than 15×109/l, lymphocyte count less than 0.6×109/l (lymphopenia), and albumin less than 4.0 g/dl as prognostic parameters [12].

We studied 175 newly diagnosed cHL cases retrospectively to evaluate prevalence and characteristics of extranodal cHL (clinically, laboratory, and radiologically). Extranodal disease was diagnosed in 28% of cases (one patient was stage IE and 48 patients were stage IV). This finding displayed that primary extranodal HL is still a rare presentation, whereas secondary extranodal HL is more common. Gaudio et al. [6] published a retrospective study on 341 patients diagnosed with HL and found that 55 (16%) patients had extralymphatic HL, seven (2%) patients were early-stage extralymphatic HL, and the other 48 (14%) extralymphatic patients were advanced stage HL. Das et al. [4] found that prevalence of ENL is increasing in both non-Hodgkin’s lymphoma and HL after retrospective study of 281 PET/CT scans.

We found the liver and lungs were the commonest extranodal sites, followed by the bone. Gaudio et al. [6] found the commonest sites were lung, bone, and liver, whereas Das et al. [4] published that the most frequently involved extranodal site was the bone.

Additionally, we found that most extranodal HL cases were diagnosed in patients less than 45 years old (85.71%). Extranodal cHL was associated significantly with unfavorable clinical features (advanced stage, spleen involvement, and IPS ≥3, with P <0.001), and decreased overall response rates (CR/PR) (P=0.025). These results are similar to Gaudio et al. [6], who found that 15% of patients with extralymphatic HL were more than 60 years old and extralymphatic presentation was statistically associated with advanced stage, spleen involvement, IPS more than or equal to 3 (also, P<0.001 for each), B symptoms (P=0.003), bulky disease (P=0.025), and response rate (P=0.043).

To our knowledge, this is the first study to reveal the relationship between extranodal presentation in cHL and MLR. Extranodal HL is highly statistically associated with elevated MLR (P<0.001). Some possible explanations could be that monocytes play an important role in the suppression of host immune response against the tumor and enhance tumor invasion and survival in lymphoproliferative disorders [13], whereas lymphocytes mediate antibody-dependent cell-mediated cytotoxicity and commonly indicate active host immune response against tumor [14].

Absolute lymphocyte count (ALC) and absolute monocyte count (AMC) might predict the outcomes in extranodal NK/T-cell lymphoma [15], Hodgkin’s lymphoma [14], and diffuse large B-cell lymphoma [16].

Unlike Gaudio et al. [6], our results did not show that extralymphatic disease is independent predictor of DFS. Moreover, univariate analysis of factors affecting OS revealed that advanced stage, extranodal sites, IPS more than or equal to 3, and high MLR (P<0.001, P=0.001, P<0.001, and P=0.004, respectively) were associated with decreased OS, whereas multivariate analysis showed only the stage (P=0.04) and IPS (P=0.008) were independent factors affecting OS ([Table 2], [Table 3]). Our results can be explained by the fact that most extranodal patients (48/49) were at stage IV. Vassilakopoulos et al. [17] recommended more studies on ALC/AMC before widespread application and its validation as a prognostic marker in cHL, with no standardized cutoff (commonly proposed cutoffs are 1.1, 1.5, and 2.9). Koh et al. [18] published that ALC/AMC ratio less than 2.9 is not an independent marker for EFS, but it is a prognostic marker of OS in patient with limited-stage cHL (P=0.011), but in patients with advanced stage, P value was not statistically significant (P=0.175).

Porrata et al. [14] published that ALC/AMC ratio more than or equal to 1.1 during any cycles of ABVD protocol was a prognostic marker of OS and PFS in 476 patients with cHL studied retrospectively. On the contrary, Romano et al. [19] confirmed that interim PET/CT is a better predictor of outcome than lymphocyte-monocyte ratio at cutoff 1.1, and lymphocyte-monocyte ratio at cutoff 3.5 lost its prognostic significance when it was analyzed in a large cohort of 1079 patients [20].

  Conclusion Top

In conclusion, we found that most extranodal cHL cases were secondary (97.96%) and had unfavorable clinical features and lower response to standard treatment. Both extranodal cHL and MLR lost their statistical significance as predictors of OS using multivariate analysis. To our knowledge, this is the first study to demonstrate extranodal cHL was statistically associated with elevated MLR.

Finally, the main limitations of our results were being a single-center experience, retrospective study, with relatively small sample size. So, further validation in a larger prospective well-designed study is required.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3]


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