Epidemiologic studies suggest that the distribution of lymphoma subtypes differs strikingly by geographic variations. However, there is limited information on this research in Northern Iran. This report demonstrates the most extensive descriptive study of subtype distribution of lymphomas classified by the WHO criteria in a single institution in Iran.
Recent studies have reported HL frequency among other types of lymphoma to be less than 10% in various regions [10– 12]. The latest research on cancer statistics in US HL made up 9.59% of all lymphomas . In our observation, this figure was 27.5%, with all cases being CHL except for two that were NLPHL. With other studies in Iran reporting higher than worldwide average HL frequency among other types of lymphomas (10 ~ 40%) [3, 4, 14, 15], it can be said that Iran has one of the highest HL proportions among other lymphomas in the world. Other countries in the regions of Middle East and North Africa, such as Jordan, Iraq, Bahrain, and Lebanon have also reported high percentages of HL, ranging from 24 to 39%, indicating a similar HL distribution pattern [16– 19]. This difference can be due to Iran’s population structure, as children and young adults comprise the majority of Iran’s population. In Western countries, HL shows a bimodal age distribution with a peak incidence in the third and sixth decades of life. In contrast, a high incidence in childhood is seen in developing countries. In addition, HL shows a gradual decline in cases with age in this series, consistent with what was seen in China [15, 16, 20, 21].
BCL compromised 61.6% of all lymphomas reported in this study, similar to those reported in MENA countries [17, 18, 22]. However, a greater number was reported in most East Asian countries such as South Korea (72.5%), China (64.4%), Sri Lanka (65.1%), and Thailand (78.3%) [23– 26]. BCL constitutes a large portion of NHL in US (83.5%) and Europe (79.9%) as well [27, 28].
In accordance with the literature, DLBCL is the most common subtype of B-cell lymphomas in Iran, with SLL being the second in this report. However, BL was the second most common subtype in another study investigating southern Iran .
Previous studies reported FL as the second most common NHL subtype with slightly varying percentages . However, in several newer studies, SLL/CLL has been reported as the second most common NHL subtype. Al-Hamadani et al. examined the data of about half a million NHL cases registered in the US from 1998 to 2011, and DLBCL (32.5%), CLL/SLL (18.6%), and FL (17.1%) were the three most common subtypes in US .
Geographical variation in FL distribution has long been recognized. This difference in follicular lymphoma incidence is attributed to different molecular pathways that lead to lymphoma in patients from different regions. There is also the possibility that some cases were diagnosed only after transformation to diffuse large B-cell lymphoma due to a lack of significant symptoms in low-grade lymphomas. This was inferred by the significantly lower incidence of bcl2 gene rearrangements, the hallmark of FL, in Asian compared to western countries. Naresh et al. proposed that the lower rates of FL compared to DLBCL in developing countries may be due to many DLBCLs having progressed from previously undiagnosed FLs, besides the unique regional, genetic, or environmental factors that might have contributed to such progression [18, 19, 30].
One known major risk factor for mature BCL is immune system abnormality. Immune deficient patients have a markedly increased risk of BCL, particularly DLBCL and BL. Some autoimmune diseases such as Sjogren’s syndrome or Hashimoto’s thyroiditis are also associated with an increased risk of developing BCLs [31, 32].
It is commonly thought that mature T cell neoplasms display higher rates in the Asian continent than in others. Therefore, racial predisposition has been proposed as a risk factor for T/NK lymphomas .
The current study and similar reports from some of the surrounding Middle East countries, as well as the western countries, show a low relative proportion of T-cell lymphomas. This is in contrast to its high proportion in East Asian countries like Japan, China, and Korea, constituting 27 − 30.5% of NHLs. While in our population, T/NK lymphomas were seen in under 10% of patients. Therefore, racial predisposition has been proposed as a risk factor for T/NK lymphomas [34, 35]. Such significant variation in the geographical distribution of T-cell lymphomas has long been recognized and has been attributed to racial predisposition, HTLV-I viral infection, and lower relative incidence of B-cell NHL in the Far East .
A previous large multicenter retrospective study confirmed the geographic variations and reported the high frequency of ATLL in Japan, AITL and ETCL in Europe, ALCL and ALK-positive in North America, and ENKTCL in Asian countries other than Japan .
As for age-specific incidence, two peaks were seen in precursor lymphoma and TCL age distribution; however, the reported frequency of these subtypes are very low, and no robust generalization can be made. No other bimodal distribution was found for other types of lymphomas.
HL exhibits a gradual decrease in cases with age in this study, consistent with what was seen in China. In contrast, a bimodal age curve (a mode at 15 ~ 35 years of age and the second mode in elderly) is apparent in North America [21, 24].
In our study, similar to other reports, a male preponderance was seen in most lymphoma subtypes [24, 34, 37]. This difference was more prominent in TCL and precursor lymphoma cases.
In this study, Extranodal involvements were seen in 20.6% of HL cases and 49.3% of NHL cases. Different countries of the world have reported varying frequencies of extranodal lymphoma cases, for example, India (22%), Iraq (48.3%), China (53.5%), and Korea (53.5%) [18, 24, 38, 39]. Diverse definition criteria, ethnic and genetic factors may cause the fluctuating frequency of extranodal lymphomas.
As reported in previous studies, DLBCL is the most common extranodal lymphoma, which is consistent with our results (37.8%) [38, 40]. Additionally, in this study, extranodal NHL most commonly involved bone marrow, whereas the GI tract, Waldeyer’s ring, nose, and sinuses are the common sites in the literature [41, 42]. Geographical differences in Helicobacter pylori incidence also may play a key role in this difference. The fluctuating frequency of extranodal lymphomas may also be caused by genetic and ethnic factors and diverse definition criteria .
In nodal involvement, some lymph node sites have shown a disproportionate prevalence of specific lymphoma subtypes. Laurent et al. examined 938 lymphoma cases in France and the most frequent sites were cervical lymph nodes (36.8% of all cases), inguinal lymph nodes (16.4%), axillary lymph nodes (11.9%), and supraclavicular lymph nodes (11%) .
The frequency of lymphomas in Iran is rising, and the increasing trend seen in previous studies in Iran and other countries was also seen in our study . Global patterns of non-Hodgkin lymphoma were studied by Miranda et al., and it was reported that most populations exprienced stable or barely increasing incidence rates . Singh et al. predicted a 30% increase in HL cases for 2040 reaching 107,000 cases .
Considering that the lymphoma cases, including consultation cases, were referred from all North West regions of Iran, the findings may represent the distribution of lymphoma subtypes in Northern Iran.