Hodgkin lymphomas in HIV/AIDS patients when treated with combined
antiretroviral therapy: further studies are needed for understanding
the pathogenesis of developing hodgkin lymphomas in HIV
Dear Editor,
I read an interesting article published in your journal titled: Malignancies
in HIV/AIDS patients attending an outpatient clinic at Santa Casa de Misericodia
de Vitória, State of Espirito Santo, Brazil by Lauro Ferreria da Silva Pinto et al. published in Revista da Sociedade Brasileira de Medicina Tropical/Journal of the Brazilian
Society of Tropical Medicine, Volume 45, November–December, pp. 687-690, 2012.
I wish to share my views on this article, especially on the Hodgkin lymphomas (HL) in HIV patients treated with combined antiretroviral therapy (cART).
Antiretroviral therapy (ART) for HIV-infected patients has definitely improved
the survival of patients. However, the long-term use of ART has some adverse
effects. The widespread use of cART since the mid 1990s has led to a significant
decrease in Kaposi sarcoma and lymphomas1.
In the current cART era, an increased mortality rate caused by several non-AIDS
defining malignancies (NADM), such as cervical cancer, lung cancers, laryngeal
cancer, colonic adenocarcinomas have been observed. This author has also
diagnosed these NADMs in the cART-treated HIV-infected population in the
provinces of the State of West Bengal, India, while serving as a Professor
in Pathology in Tertiary Care at the Post Graduate Teaching Hospital of Kolkata,
West Bengal, Institute of Post Graduate Medical Education & Research, Kolkata
(IPGMER) during 2002-2010. One case of renal cell carcinoma (RCC) was also
detected. Bidi (raw tobacco) smoking (> 30 per day) is very common among
the HIV-infected population (having < 200 CD4 count) who are from a very
low socioeconomic stratum putting them at high risk of lung and laryngeal
cancers (Squamous-cell carcinoma - SCC). Here, the majority of HIV patients
were treated with nucleoside reverse transcriptase inhibitors (NRTIs) while
some were treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs).
As a histopathologist, I have reported non-Hodgkin lymphomas (NHL), of which
7 cases were immunohistochemically proved to be of diffuse large B-cell
(DLBCL type) and one case of mycosis fungoides (T-cell type). However,
surprisingly no primary brain NHL was detected in my long career of 25 years
since 1987 as a histopathologist in Kolkata.
Interestingly, though Lauro Ferreira da Silva Pinto's study of 730 patients
found only 4 cases of NHL and 2 cases of HL (histological type not mentioned)
in a study (an MD thesis under my guidance in pathology), of 52 cancer cases
detected in HIV/AIDS patients undergoing cART therapy, we found nine (18%) cases
of HL. In these cases that were presented with fever, lymphadenopathy,
hepatomegaly, and other systemic manifestations, the cervical lymph node
biopsies showed that seven cases were of a mixed-cellular type and two cases
were of the lymphocytic depletion type within a median duration of treatment
of 3-4 months.
Incidences of HL seem and probably significantly rising unnaturally in the
HIV-infected population of the West Bengal Provinces in India more than
the conventional B-cell NHL cases, which we have known so far from CDC.
Is this owing to the fact that cART was started in Kolkata in 1996?
Alternatively, is it because of immune suppression or the
Epstein bar virus (EBV) infection in the cART patients? No studies on this
aspect can be found in the literature from India.
Studies in the United States (US) and in the
United Kingdom have probably also reported the increase in the incidence of
HL when compared with the pre-cART era. For example, among the people with
AIDS in the US, incidences of HL were shown to be elevated 8-fold compared
with the general population during the pre-cART era, and this increased
significantly to 13-fold during the cART era2. Excess risk of HL in the
US population and among the HIV-infected population in France was also
shown to be very high during the pre-cART era. In a French study, HL
incidence increased even more (by 1.4-fold) during the cART era when
compared with the pre-cART era3. In a Swiss HIV cohort study4, HL risk was
shown to be 3-fold higher in the cART era when compared with the pre-cART
era in an analysis of the first 18 cases, but this was not, however,
statistically significant and no increment in the cART era was found in an
updated analysis of 47 HL cases.
Is increased HL in the cART era postulated to be related to the actual use of
cART with a possible and potential role for certain immunologic mechanisms?
Some support for an effect of cART on HL risk was provided by the British5
and initial Swiss studies, but these finding were marginally significant and
were adjusted little or not at all by considering immune deficiency.
The British study5 on the other hand suggested that excess risk of HL might
specifically be related to the use of NNRTIs. Immune perturbation and its
control by cART are likely to be integral to the development of HIV-associated HL.
The relative risk of HIV-associated HL is 3.5-fold higher after AIDS onset,
and a lower CD4 lymphocyte count generally predicts a higher incidence of HL.
However, with the most severe immune deficiency (< 50 CD4 cells/mm3), HL risk
appears to be paradoxically lower. Why? The risk of HL increased significantly
by 2.6-fold during the first three months of cART as per the author's experience
and data! This increase may largely be explained by the concurrent CD4 cell count,
because this association with duration on cART was greatly attenuated when
we included the CD4 count in the same model. Our results also highlight
the importance of immuno suppression in the development of HL because when
compared with HIV-infected people with a CD4 count of at least 500 cells/mm3
the HL risk was increased by nearly 10-fold in those with a CD4 cell count of
50-99 cells/mm. Instead, the author suggests here that the increase in HL
incidence during the first 3-6 months on cART implies that the clinicians
in West Bengal and in the Indian tropics should be highly alert to
the possibility of developing HL during cART-induced immune reconstitution.
Corroboration and basic understanding of changes in CD4 counts,
possibility of EBV in developing HL, and releases of chemokines
during immune reconstitution (which we pathologists term as immune reconstitution
inflammatory syndrome - IRIS) might provide an insight into the pathogenesis
of developing HL amongst HIV patients treated with cART. Further research
by histopathologists and hematologists on HIV-associated HL is thus needed
in India to establish the cause for HL occurrence and its mechanism.
