Of the four cases that we describe herein, the regressed lesions of case 1 (relapsed), case 3 (relapsed), and case 2 were confirmed by pathological analysis to be MCL. Although the cervical lesion in case 4 was not confirmed pathologically, we believe that these regressed lymph nodes were highly suspicious for MCL. None of the four patients had a history of ongoing infection, antibiotic use or corticosteroid therapy use for any other diagnosis, any of which could have contributed to disease regression. In addition, no vaccination against any organism was given during the follow-up before regression.
All of the cases presented with good prognostic factors, including low Ki-67 values, low MIPI scores, and non-blastoid cytology. Tumor proliferation is recognized as a strong biological prognostic factor for MCL. Hoster et al. [5] reported differences in time-to-treatment failure and overall survival (OS) between groups with a Ki-67 value of < 30% and ≥ 30% among 543 patients studied. Furthermore, the modified combination of the Ki-67 index and MIPI (MIPI-c) separated 508 patients into four groups with 5-year OS rates of 85, 72, 43, and 17% (P < 0.001), and this combination of parameters was more discriminative than MIPI alone [6]. Our cases had a very low simplified MIPI with a Ki-67 value of < 30% (Table 1). In addition, the low SUV in PET/CT has been associated with an indolent clinical process: comparisons between SUVmax > 5 and < 5 in MCL patients have shown that the former group has decreased OS and failure-free survival [7]. Except for case 1, who presented with an SUV > 5 on PET/CT, all cases had an SUV of < 5 on PET/CT.
SR has been frequently reported in indolent lymphomas, including mucosa-associated lymphoid tissue lymphoma [8,9,10,11] and low-grade follicular lymphoma [12]. Compared with indolent lymphoma, aggressive non-Hodgkin lymphoma has a relatively low rate of SR [2]. In addition to non-Hodgkin lymphoma, SR has also been reported in classic Hodgkin lymphoma [13]. However, no case of complete SR has been reported in MCL, and only one case of MCL monitored by serial FDG-PET has been reported, which exhibited a significant but partial reduction in FDG uptake on serial whole-body PET scans, suggesting partial regression [4].
As shown in Table 1, the characteristics of the four cases demonstrated indolent behavior and low risk of progression. Interestingly, case 1 progressed after a brief follow-up and required therapy, which is not expected in indolent lymphomas; however, it was later determined that the recurrence had regressed spontaneously.
Possible mechanisms of SR reported in B cell neoplasms include an augmented host immune response through humoral and cellular immunity [2, 14]. For instance, post-allogeneic transplant lymphoproliferative disorders, usually of the aggressive large-cell lymphoma subtype, can be controlled by reducing and/or stopping the immunosuppressing agents [15]. Furthermore, the addition of the immune stimulator interferon-alpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive follicular lymphomas not only increases progression-free survival but also prolongs OS [16]. The microenvironment in follicular lymphomas has also been reported to play a role in their susceptibility to immune manipulation [17], and recent data support the importance of the microenvironment (which contains immune effector cells) in the survival of MCL cells [18].
The antitumoral response may also be inhibited or stimulated by the reaction of the immune system to the presence of contemporaneous bacteria or viruses or a traumatic intervention [2, 17]. For example, a patient with plasmablastic lymphoma achieved SR after being given antiretroviral therapy against human immunodeficiency virus infection, presumably through the restoration of immune function [19]. In another postulated mechanism of SR in plasmablastic lymphoma, mobilization of the immune system against infection with the Epstein–Barr virus caused tumor regression [20]. A traumatic intervention such as a biopsy can also induce a regional increase in immune system activity and secondary antitumoral activity with subsequent SR [21].
The antitumoral activity of the immune system is believed to be mediated through cytotoxic T lymphocytes [21, 22]. A case report of SR in a patient with diffuse large B-cell lymphoma involving the right breast suggested that CD8-positive T cells might have contributed to the regression [22]. Moreover, in SR of primary cutaneous diffuse large B-cell lymphoma, leg type, immunohistochemical studies demonstrated the presence of lymphocytes positive for CD3, 4, and 8, cytotoxic molecules, granzyme B and T-cell-restricted intracellular antigen (TIA1), both in the vicinity of the tumor nest and in the tumor [21].
A more recent and exciting confirmation of the importance of the immune system, and of T cells in particular, in the treatment of lymphoma is chimeric antigen receptor (CAR) T-cell therapy [23, 24]. Kochenderfer et al. [23] reported that chemotherapy-refractory B-cell malignancies were successfully treated with anti-CD19 CAR T cells. However, data regarding CAR T-cell therapy for MCL are scant. In mouse xenograft models, CAR T cells can be activated by CD19 antigens expressed on the MCL cell surface [25], and MCL cells are sensitive to the CTL019 (cytotoxic T lymphocytes targeting CD19 antigens) effector function. There are currently two ongoing CAR T-cell clinical trials (KITE-C19-102 and KITE-2015-0372) at MD Anderson for the treatment of relapsed or refractory MCL, which have demonstrated promising results thus far (data not published).
