**1. Introduction**

Classic Hodgkin lymphoma (CHL) stands out among malignant tumors, by the relative paucity of the tumor cells in the involved lymph nodes. These Hodgkin and Reed-Sternberg (H/RS) cells (**Figure 1**) are distributed unevenly within the majority of inflammatory cells, fibrosis and necrosis [1]. It is understood that, independent of the proportion of H/RS cells in CHL, the outcome of the malignancy will be favorable, with a cure rate of 75–90% [2, 3]. Such a therapeutic success is unusual for cancer at large.

When considering the many prognostics and risk factors regarding CHL, the stage of the tumor, as expected, is the most relevant. Evidence of systemic symptoms: fever higher than 38°C for at least a month; weight loss of more than 10% of body weight, lasting 6 months or more, and/or drenching night sweats, singly or collectively, worsen the prognosis [1]. A difference is described between genders, as females fare as a rule better than males, no consideration being given to a higher incidence of nodular sclerosis CHL in females. Indeed, children and older adult males with mixed cellularity CHL, especially in developing countries, get on worse with the disease [2, 4]. In contrast, females would be included in the bulk of CHL patients, aged 15–36, with a favorable outcome [5].

#### **Figure 1.**

*Section of lymph node from a patient with classic HL. Off center is a Hodgkin/Reed-Sternberg giant tumor cell (H&E × 360).*

Some 15-20% of human cancers are thought to arise by mechanisms which concern viruses, bacteria, or parasites [6, 7]. Evidence for their involvement comes partly from the detection of the microorganism in biopsies and partly from epidemiological and animal studies. Viruses might modify cellular genes directly, as with RNA tumor viruses, or may affect cell proliferation, as with DNA tumor viruses, and thus contribute to neoplasm formation [6, 7]. As a rule, the virus is responsible for only a limited number of steps in the promotion or progression of cancer. In most cases, the precise role of cancer-associated virus is hard to decipher, due to the long delay from the initial viral infection [6]. In any case, the number of human beings infected with the above viruses is much larger by far from that of patients who develop cancer. Therefore, tumor viruses probably act in conjunction with additional factors [7].

Chronic inflammation may play an important role in the above processes as well as in other pathologic events which may lead to cancer [8]. In some cases of unresolved chronic inflammation, the immune response becomes maladaptive, hence promoting tumorigenesis [8]. A regenerative process supported by an array of bioactive mediators, promote cell survival, tissue remodeling, and angiogenesis. The mediators will also cause genomic stress and mutations [9].

A correlation between CHL and the Epstein-Barr virus (EBV) has been demonstrated many years ago [10, 11], with a causal relationship being established as soon as 2001 [12]. The incidence of EBV infection in CHL has shown a wide geographic variation, from 17 to 30% in industrialized countries, to as high as 100% in some developing countries [13, 14]. Several more years elapsed before the distribution of EBV infection by gender, age, and CHL type was determined (**Figure 2**) [13, 14]. Thus, EBV is expressed more frequently in males, notably in children from developing countries, as well as in older adults all over the globe, these two groups showing as a rule mixed cellularity CHL. Female CHL patients stand out, in general, by showing nodular sclerosis CHL with a markedly lower level of EBV expression and a young adult age (15–36) [15]. A small subset of young adult males will develop CHL after recovering from infectious mononucleosis [16]. The EBV is recognized as oncogenic. Specifically, its transforming potential, with cell proliferation, inflammation, and apoptosis arrest, has been related to the nuclear factor-κB (NF-κB) and the EBV/LMP1 will further contribute to the inhibition of the H/RS cell apoptosis [15–19]. As noted, EBV does not play a significant role in the largest subset of CHL that affect young adults and most of the female CHL patients.

**139**

**Figure 2.**

recalled to various extents of those of CHL.

but it may be long lasting [12].

*A Role for the Measles Virus in Oncology DOI: http://dx.doi.org/10.5772/intechopen.84342*

The above subset of young adult female patients corresponds to that defined in the hallmark epidemiological studies in the early 1980s as patients with the "late host response model" [15–19]. These patients are considered to be submitted to the late exposure to a common infectious agent, the term "late" meaning that instead of coming across the common infectious agent for the first time in early childhood, this occurs at adolescence or young adulthood. The epidemiological thesis further suggests that these individuals had a late encounter with the agent, since they had few and late contacts with other children (single child, individual family house, and child who skipped the kindergarten) [15]. To account for the late host response model, it is suggested that a common agent, probably a virus, reaches the organism for the first time at a stage in which the metabolism and/or the hormonal balance is markedly different from that of a toddler, the age at which the encounter regularly takes place. At this point, the internal environment has varied deeply and probably, so has the immune system [15–19]. Thus, it seems that the EBV plays a relatively minor role, in the largest subset of the CHL that is most prevalent in industrialized countries [18]. When looking for a substitute for the EBV in CHL, it was observed that none of the additional viruses, HHV-6, -7, -8, polyoma JC virus, SV40, HTLV-1 and -2, and human retrovirus 5, once considered as possible candidates, have been detected in CHL tissues [20–26]. The only virus to be incompletely excluded at that time was the HCMV. However, one distinct virus showed qualities and associations which

*Association between age, gender, EBV expression, and classic Hodgkin lymphoma, including the types thereof.*

The "candidate" proposed by us is the measles virus (MV). It penetrates the organism through the oropharynx. But, since it is lymphotropic, it enters the adjacent lymphoid tissues. This may account for the vast majority of CHL starting in cervical and/or in mediastinal lymph nodes [12, 27]. Histologically, it elaborates multinucleated cells—the Warthin-Finkeldey polykaryons. Of note, these polykaryons differ largely from the H/RS cells of CHL, mainly by the number of nuclei (up to 70) as well as by their phenotype (they are T-lymphocytes) [28]. An acute measles infection is soon followed, on the one hand by a life-long specific immunity, but also, paradoxically a transient cellular immune deficiency systematically develops. This deficiency lasts about 6 months, but at times, may last longer. The cellular immune deficiency which affects CHL patients is not different in principle,

*A Role for the Measles Virus in Oncology DOI: http://dx.doi.org/10.5772/intechopen.84342*

#### **Figure 2.**

*Viruses and Viral Infections in Developing Countries*

Some 15-20% of human cancers are thought to arise by mechanisms which concern viruses, bacteria, or parasites [6, 7]. Evidence for their involvement comes partly from the detection of the microorganism in biopsies and partly from epidemiological and animal studies. Viruses might modify cellular genes directly, as with RNA tumor viruses, or may affect cell proliferation, as with DNA tumor viruses, and thus contribute to neoplasm formation [6, 7]. As a rule, the virus is responsible for only a limited number of steps in the promotion or progression of cancer. In most cases, the precise role of cancer-associated virus is hard to decipher, due to the long delay from the initial viral infection [6]. In any case, the number of human beings infected with the above viruses is much larger by far from that of patients who develop cancer. Therefore, tumor viruses probably act in conjunction with additional factors [7]. Chronic inflammation may play an important role in the above processes as well as in other pathologic events which may lead to cancer [8]. In some cases of unresolved chronic inflammation, the immune response becomes maladaptive, hence promoting tumorigenesis [8]. A regenerative process supported by an array of bioactive mediators, promote cell survival, tissue remodeling, and angiogenesis.

*Section of lymph node from a patient with classic HL. Off center is a Hodgkin/Reed-Sternberg giant tumor cell* 

The mediators will also cause genomic stress and mutations [9].

CHL that affect young adults and most of the female CHL patients.

A correlation between CHL and the Epstein-Barr virus (EBV) has been demonstrated many years ago [10, 11], with a causal relationship being established as soon as 2001 [12]. The incidence of EBV infection in CHL has shown a wide geographic variation, from 17 to 30% in industrialized countries, to as high as 100% in some developing countries [13, 14]. Several more years elapsed before the distribution of EBV infection by gender, age, and CHL type was determined (**Figure 2**) [13, 14]. Thus, EBV is expressed more frequently in males, notably in children from developing countries, as well as in older adults all over the globe, these two groups showing as a rule mixed cellularity CHL. Female CHL patients stand out, in general, by showing nodular sclerosis CHL with a markedly lower level of EBV expression and a young adult age (15–36) [15]. A small subset of young adult males will develop CHL after recovering from infectious mononucleosis [16]. The EBV is recognized as oncogenic. Specifically, its transforming potential, with cell proliferation, inflammation, and apoptosis arrest, has been related to the nuclear factor-κB (NF-κB) and the EBV/LMP1 will further contribute to the inhibition of the H/RS cell apoptosis [15–19]. As noted, EBV does not play a significant role in the largest subset of

**138**

**Figure 1.**

*(H&E × 360).*

*Association between age, gender, EBV expression, and classic Hodgkin lymphoma, including the types thereof.*

The above subset of young adult female patients corresponds to that defined in the hallmark epidemiological studies in the early 1980s as patients with the "late host response model" [15–19]. These patients are considered to be submitted to the late exposure to a common infectious agent, the term "late" meaning that instead of coming across the common infectious agent for the first time in early childhood, this occurs at adolescence or young adulthood. The epidemiological thesis further suggests that these individuals had a late encounter with the agent, since they had few and late contacts with other children (single child, individual family house, and child who skipped the kindergarten) [15]. To account for the late host response model, it is suggested that a common agent, probably a virus, reaches the organism for the first time at a stage in which the metabolism and/or the hormonal balance is markedly different from that of a toddler, the age at which the encounter regularly takes place. At this point, the internal environment has varied deeply and probably, so has the immune system [15–19]. Thus, it seems that the EBV plays a relatively minor role, in the largest subset of the CHL that is most prevalent in industrialized countries [18].

When looking for a substitute for the EBV in CHL, it was observed that none of the additional viruses, HHV-6, -7, -8, polyoma JC virus, SV40, HTLV-1 and -2, and human retrovirus 5, once considered as possible candidates, have been detected in CHL tissues [20–26]. The only virus to be incompletely excluded at that time was the HCMV. However, one distinct virus showed qualities and associations which recalled to various extents of those of CHL.

The "candidate" proposed by us is the measles virus (MV). It penetrates the organism through the oropharynx. But, since it is lymphotropic, it enters the adjacent lymphoid tissues. This may account for the vast majority of CHL starting in cervical and/or in mediastinal lymph nodes [12, 27]. Histologically, it elaborates multinucleated cells—the Warthin-Finkeldey polykaryons. Of note, these polykaryons differ largely from the H/RS cells of CHL, mainly by the number of nuclei (up to 70) as well as by their phenotype (they are T-lymphocytes) [28]. An acute measles infection is soon followed, on the one hand by a life-long specific immunity, but also, paradoxically a transient cellular immune deficiency systematically develops. This deficiency lasts about 6 months, but at times, may last longer. The cellular immune deficiency which affects CHL patients is not different in principle, but it may be long lasting [12].

At the time our thesis was formulated, the type of MV neural infection known as subacute sclerosing panencephalitis (SSPE) was considered one of the very few persistent MV infections, most being CNS slow viral infections. However, it was difficult to grasp a possible association between MV and cancer, which would not account for the long lapse of time necessary for the malignant transformation. In that context, the absence of a persistent MV infection might be counterproductive. The alternative being that against all odds, MV may be oncogenic, and the MV is not among the consensually recognized oncogenic viruses! An additional clue to MV causing a persistent infection beyond the CNS is the absence of membrane expression of hemagglutinin MV antigens, although this lack of expression might be due also to the lymph node mode of fixation [29].
