Clinico-Pathological Study of Hodgkin's Disease in King Abdulaziz University Hospital, Jeddah

Edited by Foxit Reader Copyright(C) by Foxit Software Company,2005-2007 For Evaluation Only. CLINICAL STUDIES Clinico-Pathological Study of Hodgkin's Disease in King Abdulaziz University Hospital, Jeddah Fatin Mohammed Omer Al-Sayes FRCPath, Ali Sawan Ph D* Department of Haematolog, * Department of Pathology, King Abdulaziz University Hospital Jeddah, Kingdom of Saudi Arabia Abstract: Hodgkin s disease (HD) has unique epidemiological features with diversified pathologies. The aim of this study was to investigate the clinicopathological pattern of HD at King Abdulaziz University Hospital (KAUH), Jeddah. Our results will be compared to those in the literatures. In addition, the relationship between peripheral blood lymphopenia on presentation, and clinical and laboratory variables among HD patients will also be addressed. A total of 81 HD patients were included in this study. The records were analyzed retrospectively from January 1998 through December 2004 and recorded in a structured form. In order to determine the importance of lymphopenia on presentation as a diagnostic marker in HD a comparison was made to a similar number of patients with non-hodgkin s lymphoma (NHL) after standardization for age, sex and clinical presentation. Moreover, the association between lymphopenia and clinical and laboratory variables were also studied. There were 54 (66.7%) non-saudi and 27 (33.3%) Saudi patients with a male to female ratio of 1.3:1. The mean age of the patients was 40.4 years, ranging from (12-82) years with a SD of 18.95. Cervical lymph nodes were the most common finding at the time of presentation. Mixed cellularity was the most frequent pathology followed by nodular sclerosis with prevalence of advanced stages of the disease in 48 (59.2%) and B symptoms 67 (82.7%). Lymphopenia was seen in 33 patients, 24 (72.7%) of them were above the age of 30. A comparison between Hodgkin s disease and non-hodgkin s lymphoma regarding lymphopenia, using the same number of patients after standardization for age, sex and presentation did not turn out to be significant (P > 0.05). Relationship between lymphopenia and other clinical and laboratory variables also did not turn out to be significant with the exception of anemia where the P-value was <0.05. Our data demonstrated that HD is more common among males, mainly at middle age with lack of bimodal age distribution. Cervical lymphadenopathy is a common presenting sign. Similar to other developing countries the mixed cellularity type of HD was the most common type followed by the nodular sclerosis type. Lymphopenia on presentation is common among patients with HD especially above the age of 30. In order to analyze the importance of this finding as a diagnostic marker in HD, a comparison was made to NHL patients but the association was insignificant. The relationship between lymphopenia and anemia among HD patients is significant as compared to other clinical and laboratory variables. Keywords: Epidemiology, Histopathology, Hodgkin's disease, Lymphopenia :48-56 Correspondence to: Fatin Mohammed Omer Al-Sayes Department of Hematology, King Abdulaziz University Hospital PO Box 80215, Jeddah 21589 Kingdom of Saudi Arabia E-mail: fatinsayes@yahoo.com 48

Al-Sayes and Sawan Introduction Hodgkin s disease (HD) is a relatively rare malignancy which was initially described by Thomas Hodgkin in 1832 [1]. It occurs in males more commonly than females (sex ratio approximately 1.4:1). It has a bimodal age distribution demonstrated in industrialized populations with one peak in the 20 s and a second peak over the age of 50. In the developing countries, the young adult peak is not seen, and instead a higher incidence of HD is seen among children less than 15 years of age [2]. There are important observations that correlate socioeconomic factors and disease incidence [3]. Reports of clustering of cases in a single household are frequent. Urban people with higher education seem to be more affected with the disease than others [4]. Although the etiology of HD is unknown, epidemiologic data suggest that viral factors, especially Epstein-Barr virus (EBV) may play a causal role [5]. The diagnosis of HD depends on the finding of multinucleated Reed-Sternberg (RS) cells or their variants in an inflammatory background of benign reactive cells consisting of lymphocytes, histiocytes, neutrophils, plasma cells and fibroblasts [6]. The disease has been classified using the Rye classification system into four pathological subtypes (nodular sclerosis, mixed cellularity, lymphocyte predominance and lymphocyte depleted). The most common subtype in western countries is nodular sclerosis but in Asia it is mixed cellularity [7]. The Ann Arbor staging system was adopted and generally accepted [8]. It is a four-staged disease (I, II, III, and IV) which is very crucial for analyzing the clinical and epidemiological behaviour of the disease. The presence of fever in excess of 38 o C, drenching night sweats and weight loss exceeding 10 percent of baseline body weight during the 6 months preceding diagnosis are designated as having B symptoms. Recent reports from the National Cancer Registry have indicated that HD accounted for 3.8% of all 5,616 newly diagnosed cancer cases. It ranked eight for males and 12 th for females [9]. The aim of this study was to investigate the clinicopathologic pattern of HD at King Abdulaziz University Hospital (KAUH), Jeddah, and to compare the results with those documented in the literatures. Moreover, the relationship, if any, between peripheral blood lymphopenia on presentation, clinical and laboratory variables will be also addressed. Subjects and Methods A total of 81 adult patients with HD diagnosed at KAUH between January 1998 and December 2004 were studied retrospectively. Medical records of all patients were reviewed, and clinical and pathological informations were recorded in a structured form. In order to apply Ann Arbor staging system properly, all informations were reviewed carefully including the main presenting complaints, physical examination, laboratory work, radiological assessment, histology reports, bone marrow aspiration and biopsy findings if available. Lymph node or tissue biopsy specimens were reviewed again, to be certain that they are qualified for the histologic subtypes. Immunohistochemical staining was performed using a panel of antibodies against CD15, CD30, and (CD20 and CD79a) for lymphocyte predominant histologic subtype. Lymphocyte count of cases with non-hodgkin's lymphoma, were collected and 33 patients with lymphopenia were compared to those with similar finding in NHL after standardization for age, sex and clinical presentation. 49

Clinico-Pathological Study of.. The clinical and laboratory data were processed using statistical program SPSS-V10. To obtain descriptive statistics (number and percent), analytical statistics (cross tabulation and Chi-square) were applied. P-value was considered significant at <0.05. Data were graphically represented using graphic program. All cases of HD were classified using the Rye classification system into four pathological subtypes (lymphocyte predominant, nodular sclerosis, mixed cellularity and lymphocyte depleted) [7]. Results Among the 81 HD patients, 54 (66.7%) were Non-Saudi and 27 (33.3%) were Saudi. There were 46 (56.8%) men and 35 (43.2%) women with a male to female ratio 1.31:1. The mean age of the patients was 40.4 years, ranging (12-82) years, with a SD of 18.95. The most common location of HD at the time of diagnosis was the cervical lymph nodes, 53 cases (65.9%) followed by mediastinal and abdominal lymph nodes 6 (7.3%) cases each while axillary lymph nodes were found in 3 (3.7%) patients. Only one case had primary extranodal presentation with lung involvement. Interestingly, 11 patients (13.6%) presented with B symptoms with no palpable lymph nodes. Thirty-three patients (40.7%) had histologic features of mixed cellularity, whereas nodular sclerosis was the next most frequent histologic subtype seen in thirty one patients (38.3%) followed by lymphocyte predominant in thirteen patients (16.1%), while only 3 (4.9%) patients had lymphocyte depleted histologic subtypes. Eight patients (9.9%) had Stage I HL disease; 25 (30.9%) stage II, 27 (33.3%) Stage III and 21 (25.9%) had Stage IV. Advanced stages were seen predominantly with mixed cellularity 22 (66.7%) and lymphocyte depleted histology subtypes 4 (100%) (Figure1). Sixty-seven (82.7%) patients were reported with B symptoms (fever, night sweats and weight loss). Early (9) 69,2% Early (13) 41,9% Lympho. pred. Early (11) 33,3% Adv. (4) 30,8% Nod.sclerosis Adv. (18) 58,1% Adv. (4) 100,0% Mixed cell. Adv. (22) 66,7% Early Adv. Lympho.dep. Figuer 1: Relationship between different histologic subtypes and stages of Hodgkin's disease 50

Al-Sayes and Sawan The frequency of B symptoms was highest in mixed cellularity and lymphocyte depleted histologic subtypes 28 (84.8%) respectively. Out of 77 available bone marrow specimens of HD cases, evidence of involvement was seen only in 11 (14.3%). The relationship between different histologic subtypes and bone marrow involvement is shown in (figure 2) which demonstrates that all the four cases of lymphocyte depleted histologic subtypes revealed the bone marrow involvement. Figure 3 summarizes the association between different histologic subtypes and outcome which remained inconclusive. Characteristic feature of patients with HD are summarized in table 1. Table 1: Characteristic features of patients with Hodgkin s disease Chracteristic No % Age 30 y 30 y 28 53 34.6 65.4 Sex Males Females 46 35 56.8 43.2 Race Saudi Non-Saudi 27 54 33.3 66.7 Presenting Lymph nodes: Neck/Multiple Axillary Mediastinal Inguinal Abdominal Extralymphatic B-symptoms 53 3 6 1 6 1 11 65.4 3.7 7.4 1.2 7.4 1.2 13.6 Histologic subtypes Lympho. pred. Nod. sclerosis Mixed cell Lympho. dep. Stage I II III IV 13 31 33 4 8 25 27 21 16.1 38.3 40.7 4.9 9.9 30.9 33.3 25.9 B symptoms* Positive Negative 67 14 82.7 17.3 Bone marrow Not involved Involved 66 11 85.7 14.3 * fever, night sweats & weight loss 51

Clinico-Pathological Study of.. Mixed cell Figure 2: Relationship between different hitologic subtypes and bone marrow involvement Figure 3: Relationship between different histologic subtypes and bone marrow 52

Al-Sayes and Sawan Lymphopenia was observed in 72.7% patients with HD older than 30 years. The relationship between peripheral blood lymphopenia on presentation seen in 33 patients with HD, age, sex race, stages of the disease, histologic subtypes, B symptoms, Hb, LDH, uric acid and finally outcome were studied (Table 2), and the findings were not significant with the exception of anemia which showed striking association with lymphopenia (P value <0.05). To study the significance of lymphopenia as a diagnostic marker in HD, a comparison was made using similar number of cases of non-hodgkin s lymphoma (NHL) after standardization for age, sex and presentation. The P value was >0.05. Table 2: Relationship between low lymphocyte count with clinical and laboratory variables in Hodgkin s disease Characteristic Features Age (years): (n=70) <30 >30 Sex: (n=70) Males Females Race: (n=70) Saudi Non-Saudi Stage of the disease (n=70) I and II III and IV Histopath- subtypes (n=70) Lymphocyte pred Nodular sclerosis Mixed cellularity Lymphocyte dep. B-symptoms: (n=70) Positive Negative Hb level: (n=70) Low Normal LDH: (n=60) Normal High Uric acid: (n=53) Normal High Outcome: (n=57) Cured or remission Relapse Died High Lymphocyte Low Lymphocyte Statistical Analysis No (%) No (%) Chi-square P-value 14 23 23 14 15 22 18 19 6 14 16 1 29 8 17 17 8 23 23 5 21 10 0 37.8 62.2 62.2 37.8 40.5 59.5 48.6 51.4 16.2 37.8 43.3 2.7 78.4 21.6 50 50 25.8 74.2 82.1 17.9 67.7 32.3 0 9 24 16 17 9 24 9 24 6 9 15 3 31 2 25 5 4 25 22 3 12 11 3 27.3 72.7 48.5 51.5 27.3 72.7 0.46 >0.05 0.83 >0.05 0.83 >0.05 27.3 72.7 2.50 >0.05 18.2 27.3 45.4 9.1 93.9 6.1 83.3 6.7 13.8 86.2 88.0 12.0 46.2 42.3 11.5 0.01 0.47 0.00 0.40 >0.05 >0.05 >0.05 >0.05 2.29 >0.05 0.014 <0.05 0.71 >0.05 0.04 >0.05 5.1 >0.05 Disscusion In our study we reported an excess of non-saudi patients (66.7%) because KAUH is considered as a referral center in the Western region of Saudi Arabia with admission facilities of non-saudi patients, males were affected more than females with male to female ratio of 1.3:1 which is lower than what has been reported earlier from Kingdom of Saudi Arabia [10, 11] and many other developing countries [12, 13] but is close to ratio reported from the West [14]. 53

Clinico-Pathological Study of.. In economically developed countries of the West, HD is reported with a bimodal age distribution with an early peak appearing in young adulthood and another peak after the age of 50 years. Our results didn t show an increasing incidence of HD in young adults but it did show increasing frequency with advancing age, 53 cases (64.5%). Unlike similar studies from Oman, Bahrain and North Jordan which suggested a regional peak occurrence in childhood with highest frequencies occurring in first and second decade of life [13,15,16]. This may indicate that the patterns of HD are changing not only in the developed countries but also in the developing countries [11] or might be a result of lack of discrimination between HD and NHL, because some patients may fall in the category of diffuse large B-cell lymphoma after re-characterization. HD presents as cervical lymphadenopathy in 60-80% of the cases, our data revealed that neck lymphadenopathy was the most common presenting location at the time of diagnosis (65.4%) while primary extranodal involvement was very rare seen in (1.2%), which is similar to a previous study from United Arab Emirates [17]. B symptoms were found in approximately 25 percent of patients. These symptoms were more common, occurring in up to 50 percent of cases, in more advanced disease [18]. We observed the prevalence of B symptoms in HD patients to be 82.7 percent, in addition 11 (13.6%) patients presented initially with B symptoms with no palpable lymphadenopathy which suggest the importance of B symptoms as presenting signs [11]. The most frequently diagnosed entity was mixed cellularity histologic subtype (40.7%) followed by nodular sclerosis (38.3%). The results are in agreement with previous studies from Oman [13], Bahrain [15], Kuwait [19], KSA [20], Greece [21] and Turkey [22]. This pattern is different to what is seen in Western countries where the nodular sclerosis type of HD is the most common type, followed by mixed cellularity [23, 24]. Thirteen out of 33 mixed cellularity histologic subtype were above the age of 60 years with male prevalence. This discrepancy however, could have been the result of small sample group in our study. The lymphocyte depleted type of HD comprised 4.9% of HD cases, which is higher than neighboring countries [15, 16, 24]. Lymphocyte predominant type, which is now considered as a distinct entity of HD according to the recent WHO classification system of lymphoma [24], accounted for 16% of all HD cases. This figure is higher than the 2-5% figure reported in the West [24] and the 4-8.3% figure from neighboring countries [15, 25, 26]. We observed the prevalence of advanced stages of the disease (stage III, IV) in 48 (59.2%) which is similar to a previous study from the Kingdom of Saudi Arabia [11]. However, this presentation is comparatively less than a frequency range of 65-95% reported earlier from Kingdom of Saudi Arabia and other developing countries [20, 27, 28]. Lower incidence of advanced clinical stages might result from early diagnosis because of comprehensive clinical work-up and advanced imaging studies. Bone marrow involvement in HD can only be rarely demonstrated by the trephine biopsy. Bone marrow study is not indicated in the case of females with clinical stage I-II; a disease which carries extremely low incidence of bone marrow involvement [29]. In our study, bone marrow infiltration was seen in only 11 (14.3%) cases. No conclusion can be drawn from the results of treatment outcome of HD in relation to different histologic subtypes because of the small sampling in our study and the fact that some of the patients lost follow-up or still not considered as cured. Patients with HD are known to have peripheral blood lymphopenia [30]. The prognostic significance of this observation and its 54

Al-Sayes and Sawan implication on immune system remain controversial [30]. Nevertheless, peripheral blood lymphopenia was included in the international prognostic factors project on advanced HD as an important prognostic variable [31]. Lymphopenia was observed in 33 patients with HD, 24 (72.7%) of them were older than of 30 years. To determine its significance as a diagnostic marker in HD, we carried out a comparison to similar number of patients with non-hodgkin s lymphoma. There was no significant difference between the two groups of haematologic malignancies (P value >0.05). Moreover, the relationship between peripheral blood lymphopenia in HD on presentation, clinical and laboratory variables which included age, sex, race, clinical stages, histologic subtypes, B symptoms, LDH, uric acid and finally outcome were not significant. Anemia in HD is mainly normocytic-normochromic type, rarely it can be Coomb s positive autoimmune hemolytic in nature. The international prognostic factors project on advanced HD developed a seven-factor prognostic score, lymphopenia and anaemia were among them [31]. The relationship between normocytic normochromic anaemia and lymphopenia in HD in our cohort turned out to be significant (P<0.05). The reason for that is probably because both are seen in advanced stages of the disease but this finding needs to be consolidated by larger study. A notable feature in this study is a male predominance and there is no bimodal distribution of age in our hospital. Most patients present initially with cervical lymphadenopathy. Mixed cellularity is the most frequent histological subtype followed by nodular sclerosis, constitutional symptoms are reported in most of the cases. Almost two third of the cases were advanced. Lymphopenia on presentation was observed frequently above the age of 30, but it did not turn out to be a significant diagnostic marker in HD when compared to non- Hodgkin s lymphoma. The relationship between lymphopenia in HD and age, sex, race, clinical stage, histopathologic subtypes, B symptoms, LDH, uric acid and finally outcome did not turn out to be significant. A significant association is reported between lymphopenia and anemia, probably because both are reported in advanced clinical stages of the disease. The data presented here is an approximate assessment of the epidemiological features of HD at KAUH. Further studies together with national cancer registry data will probably identify epidemiology and risk factors for HD which is needed to make definite preventive and therapeutic measures. Moreover numerous reports have suggested a strong association between EBV infection and the development of HD. It will be interesting to conduct future study to assess this relationship in our hospital population using the new WHO classification. References 1. Hodgkin T. Morbid appearance of the absorbent glands and spleen. Med ChirTrans 1832; 68:17: Cited in N EngL J Med 1992; 326:678 2. MacFarlane GL, Evstifeeva T, Boyle P and Glufferman S. International patterns in the occurrence of Hodgkin s disease in children and young adult males. Int J Cancer 1995; 61:165-169 3. Gutensohn N, Cole P. Childhood social environment and Hodgkin s disease N E J Med 1981; 304: 135-40 4. Grufferman S, Cole P. Smith PG, Lukes RJ. Hodgkin s disease in siblings. N Engl J Med 1977; 296: 248-250 5. Weiss LM, Strickler JG, Warnke RA, Purtilo DT, Sklar J. Epstein-Barr viral. DNA in tissues of Hodgkin s disease. AMJ Pathol 1987; 129: 86-91 6. Yung L, Linch D. Hodgkin s Lymphoma. Lancet 2003 Mar 15; 361:943-951 7. Glaser S, Dorfman R, Clarke C. Expert review of the diagnosis and histologic classification of Hodgkin s disease in a population-based cancer registry. Cancer 2001; 92:218-224 55

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