Epidemiology of HTLV -Associated Leukemia
W. A. Blattner, D. W. Blayney, E. S. Jaffe, M. Robert-Guroff, V. S. Kalyanaraman, and R. C. Gallo    Hämatol. Bluttransf. Vol 28

A. Introduction

Type-C retroviruses have long been implicated in the etiology of leukemia and lymphoma in various animal species. Animal models exist for exogenous, horizontal, transmission of these naturally occurring RNA tumor viruses in animals and are especially well characterized for cat, cow, and some other species [21]. Human T-cellleukemia-lymphoma virus (HTL V) is the first type-C retrovirus consistently isolated and associated with specific human malignancies. It is distinct from prcviously identified animal retroviruses by molccular [15] and immunologic studies [10, 16, 17]. It is an exogenous virus that must be acquired by infection (i.e., not transmitted in the germ line), since HTLV proviral sequences are present in DNA of neoplastic T cells, but not in DNA of nonneoplastic B cells from the same patient [7] or in normal tissues [15]. In this report we summarize clinical and epidemiologic features which suggest that HTL V is etiologically linked to certain malignancies. Our data demonstrate that HTL V is associated with cases of mature T -cell leukemia-Iymphoma with common clinica] features. These cases tend to cluster in a restricted distribution whcrc HTL V infection is prevalent. Occasional paticnts from virus nonendemic areas probably acquired HTL V infection prior to developing their T -cell leukemia-lymphoma through travel into HTL V endemic areas and close contact with residents in these areas.

B. Materials and Methods

Samples from various patient and normal populations were submitted as frozen or lyophilized serum or plasma. The clinical and pathologic diagnoses were as recorded by the submitting investigator except for certain cases where pathologic material was reviewed by one of us (E.J.). Serum antibodies to a disrupted whole virus preparation were detected by a modification to thc technique previously reported [14]. Natural antibody to the major core protein p24 of HTL V was detected by a radioimmune precipitation (RIP) as previously described [9].

C. Clinical and Pathologic Features

The majority of cases from which HTL V has been isolated, or in which HTL V antibodies have been detected, share many common features. Summarized in Table I are the clinica] and pathologic characteristics of HTL V -positive cases from the Western Hemisphere and elsewhere ( details of HTL V -positive cases from Japan are not included in this report). In all cases in the series, and in cases from Japan [II, 18], HTLV has an association with lymphoma or leukemia of mature differentiated T cells. In current immunopathologic nomenclature, the broad category of malignancies of mature T cells includes T -cell chronic lymphocytic leukemia, cutaneous T -cell lymphomas (CTCL) (mycosis fungoideslSezary syndrome), peripheral T -cell lymphoma, lymphosarcoma cell leukemia (T -LCL), and adult T -cell ]eukcmia-Iym phoma (A TL). As shown in Table I, HTL V is most commonly associated with peripheral T -celllymphomas (classification in the working formulation [ I] as large cell, diffuse mixed, or immunoblastic cell type), TLCL, and A TL. Although two of these

Fig. I. a Posterior auricular lymph node from case 16. An admixture of small and large atypical lymphoid cells is present. Hematoxylin and eosin, X 430. b Plain skull radiograph for case 16. Multiple small lytic lesions are present throughout the calvarium

cases were classified as CTCL, this association is rare since they are the only two out of over 200 cases from the United States, England, and western Europe that were positive for HTL V serum antibodies. As is evident from Table I, the histopathologic diagnoses given vary considerably. There are, however, certain morphologic features shared by most of these tumors. The tissues show diffuse proliferation of a pleomorphic population of lymphoid cells (Fig. I a). The cells tend to vary considerably both in size and shape. In most cases, cells from all points in the spectrum are present in equal proportions, and such cases are designated as diffuse, mixed cell type by both the Rappaport classification and the working formulation [I]. In other cases, one large lymphoid cell type predominates, and such cases are designated as diffusc large cell, or diffuse large cell, immunoblastic lymphoma, based on the characteristics of the proliferating cells. An inflammatory background is normally not evident. The histopathologic features described above are similar to those seen with certain other peripheral T -cell lymphomas not associated with HTL V. Thus, there are no specific pathologic features that can be recognized at this point as indicating an HTL V -associated leukemia/lymphoma. Similarly, there is quite a spectrum in the clinical presentation of cases, which may present a.s lymphoma, leukemia, or lymphoma with leukemic involvement. Some cases appear associated with fulminant and rapidly progressive disease, whereas others have a much more indolent and chronic clinical course. Thus, the exact relationship of HTLV to a specific clinical entity is far from established. Therefore, systematic surveys in HTL V -endemic and nonendemic areas, with special attention to precise immunologic classification of malignant cells, will be needed to clarify thesc relationships further. In addition the recent observation ofantibody-negative, antigen-positive cases of CTCL (C. Saxinger, personal communication) point to a need for caution in defining virus-disease relationships. Ultimately "molecular" epidemiologic studies of defIned disease categories will need to be undertaken before final conclusions can be drawn.

One of the striking features of these cases [4], as well as A TL cases from Japan [20], is the frequent occurrence of idiopathic hypercalcemia. In some cases (Fig. I b) radiographs show multiplc lytic bone lesions mimicking multiple myeloma or metastatic solid tumors. In thesc cases, no lymphoma cells are sccn in association with these lesions but rather osteocla,5t activity and reactive granulation tissue. This pathologic feature may be a reflection of HTL V -activated lymphokine production, although tor cases 4, 16, and 17, the lymphokine, osteoclast activating factor (OAF) was not detectable in bioassay [3]. A variety of lymphokines are produced by HTLV-infected cell lines in vitro, suggesting that integration of proviral DNA results in derepression of host genes including those tor various lymphokines [8]. Viral-associated cases with hypercalcemia provide a convenient setting to test this model.

D. Disease Associations and Case Clusters

To evaluate the relationship of HTL V infection and disease, sera from over 900 cases of adult and childhood malignancies from diverse geographic areas have been tested for HTL V antibodies [6]. As shown in Table 2, only 55 of 914 were positive. None of the nonlymphoreticular neoplasms were positive, indicating that HTL Vis probably trophic tor cells of thc Iymphoreticular compartment. The bulk of the positives were from patients with dcfinitc T -cell malignancies. The remaining nine were from patients with lymphoid and/or myeloid leukemias from Japan. Since some of these cases come from the viral endemic area and/or in some cases have been extensively transfused, the etiologic significance of this association remains to be established. HTL V is most closely associatcd with A TL diagnosed in Japan, and 29 of the 34 patients in this series were positivc [6]. Among cases ofT -Cell non-Hodgkin's lymphoma (T -NHL), 6 of 12 from Japan were also positive. These positive T -NHL cases appear to share featurcs with cases from the United States and elsewhere as recorded in Table I. The eight cases of HTLVpositive A TL from the Caribbean region (cases 8-15 in Table I in this series) confirm the propensity for geographic clusters of HTL V -associated cases to share clinical and pathologic features [2,4]. Studies of normal populations providc a model for examining the role of HTL Vas an etiologic agent. The detection of HTL V antibodies in relatives of cases is of interest since it may reflect the infectivity ofHTLV. In Table 3 we summarize the data on members in nine families of HTL V -positivc malignancies. Excpt for one family from Japan in which four of eight members were antibody positive, in all other cascs only one first-degree relative was found to be positive. The fact that both spouses and blood relatives were positive leads us to suspect horizontal rather than vertical

transmission. Since relatives of these cases shared a common environment, prospective follow-up of exposed relatives of newly diagnosed HTL V -positive cases should help clarify the mode of HTL V transmission [19]. Limited surveys of donors from populations in the United States, western Europe, Japan, and the Caribbean (Table 3) demonstrate that HTL V infection in the general population is limited. Among study subjects from the United States and Europe only three had HTL V antibodies. The three positives were from a sample of specimens submitted to the Georgia State Health Department serology reference laboratory. Many of the United States-born cases of HTLV leukemia-lymphoma, as well as the normal people with HTL V antibodies, are blacks from the southeast United States. This geographic and racial clustering suggests that HTL V infection may have a restricted distribution and/ or racial predilection. Further analysis of other populations in this region as well as surveys in other areas of the United States should clarify this relationship [3]. In Japan, sera from A TL nonendemic regions were HTL V antibody negative, while a low prevalence of virus antibody positives was seen in the A TL endemic region of K yushu (RobertGuroff et al., unpublished observations). Similarly a population-based survey ofnormals in the Caribbean revealed a low prevalence of HTL V -positive serology [2].

E. HTLV Infection and Adult T -cell Malignancy

The frustrating failures of virologists in the past to demonstrate and isolate a uniquely human type-C RNA tumor virus etiologically linked with leukemia or lymphoma has led to the belief that retroviruses play no rolc in these or other human malignancies. Human T -cell leukemia-lymphoma virus (HTLV) is the first human virus of this class consistently identified in association with a specific type of human leukemia-lymphoma [5, 12, 13]. The epidemiologic data summarized here demonstrate that HTL V is associated with several malignancies of the T cell, but not solid tumors or other hematopoietic tumors [6]. Although the role of HTL Vas an etiologic agent is not established, it is striking that the distribution of cases is limited to a relatively narrow spectrum of mature T -cell leukemia-lymphoma cases with common features. In further support of the notion that HTL V and T -cell leukemia-lymphoma are related is the limited distribution of HTL V infection in the general population. Although most dramatic in Japan, where HTL V seropositivity appears geographically associated with clusters of A TL [ II, 18], a similar pattern is emerging in the Caribbean [2, 4] and more recently in the southeastern United States blacks [3]. In two cases from the United States (case 2, MJ, case 3, M.O.) both the clinical and epidemiologic features were distinct from the bulk of other cases. Both patients, how ever, had histories of travel to and close contact with persons in viral endemic areas. These exceptions to the rule provide further evidence for a virus-disease relationship since it is likely that their HTL V infection was acquired in viral endemic regions. Studies of migrants into HTL V endemic regions may prove especially informative in further delineating etiologic relationships. In summary, we postulate that HTLV, unlike other putative tumor viruses, is not widespread in distribution but rather is limited to certain regions of the world and within limited areas of some countries (e.g., southwestern Japan). In at least three areas, Japan, the Caribbean, and the southeastern United States, HTL V -associated disease is a mature adult T -cell leukemia-Iymphoma. Identification of cases in some other areas of the world suggests that a similar pattern of virus prevalence and disease occurrence will emerge. Thus, although further studies will be needed to establish a causal relationship, the story thus far is similar to that of the retrovirus association with leukemialymphoma in animals in which satisfaction of Koch's postulates has established an etiologic role for C-type retroviruses.


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