558
Fig. 37.6 SS-associated nodal marginal zone B-cell lymphoma (NMZL).
(a) Lymph node infiltration by NMZL is characterized by a predominant population of smallto medium-sized centrocyte-like, monocytoid B-cells and scattered transformed B-cells (H&E, × 400). (b) Staining (anti-CD21 × 200) for follicular dendritic cells (DDCs) reveals overrun follicles by showing residual
meshwork of FDCs indicative of follicular colonization. The tumor cells surround reactive follicles and expand into the interfollicular areas. These results, together with the histological findings, confirmed that the lesion represented a B-cell marginal zone lymphoma. The clinical staging confirms the diagnosis of NMZL in the absence of extranodal involvement
M. Voulgarelis and H.M. Moutsopoulos
a
b
the use of R-CHOP (a regimen comprising an anti-CD20 monoclonal antibody plus cyclophosphamide/doxorubicin/vincristine/prednisone) as a first-line treatment appears to be effective in SS patients with NMZL, although long-term results are still needed [49–51]. In young patients who experience disease relapses, autologous bone marrow transplantation should be considered [52].
37.3Diffuse Large B-Cell Lymphomas
37.3.1Histology and General Considerations
In some patients with SS, lymphomas tend to evolve toward less differentiated (higher grade) cell types [5]. The transition from benign chronic lymphoepithelial sialadenitis to indolent MALT lymphomas and possibly to high-grade lymphoma,
37 Treatment of B-Cell Lymphoma |
559 |
Table 37.3 Clinical and histological features of 26 SS patients who developed marginal zone B-cell lymphoma
|
MALT (%) |
Nodal marginal |
||
|
lymphoma |
zone lymphoma (%) |
||
|
|
|
||
Cases |
21/26 (80.8) |
5/26 (19.2) |
||
Sex |
|
|
|
|
Male |
1(4.8%) |
0 |
(0) |
|
Female |
20 (95.2%) |
5 |
(100) |
|
Age |
|
|
|
|
Mean ± SD |
50.71 ± 11.6 |
48 ± 9.4 |
||
Range |
30–74 |
37–61 |
||
Ann Arbor stage |
|
|
|
|
I–II |
16 (76.2) |
1 |
(20) |
|
III–IV |
5 |
(23.8) |
4 |
(80) |
Nodal involvement |
3 |
(14.3) |
5 |
(100) |
Extranodal |
21(100) |
1 |
(20) |
|
involvementa |
|
|
|
|
Both nodal and |
3 |
(14.3) |
1 |
(20) |
extranodal |
|
|
|
|
Bulky diseaseb |
1 |
(4.8) |
1 |
(20) |
B-symptomsc |
2 |
(9.5) |
1 |
(20) |
Splenomegaly |
2 |
(9.5) |
4 |
(80) |
Bone marrow |
4 |
(19) |
3 |
(60) |
involvement |
|
|
|
|
aParotid gland, submandibular salivary gland, lacrimal gland, lung
bTumor mass size >7 cm
cUnexplained weight loss of >10% of body weight in 6 months; unexplained, persistent or recurrent fever >38°C; recurrent, drenching night sweats
e.g., DLBCL, represents a multi-step process caused by genetic alterations such as p53 allelic loss and mutations, hypermethylation of p15 and p16 genes, and p16 gene deletions [53, 54]. The histological transformation of MALT lymphoma to DLBCL is heralded by the emergence of an increased number of transformed blasts that form sheets or clusters, which eventually effaces the preceding MALT lymphoma (Fig. 37.7). It is unclear how many DLBCLs arise from preexisting MALT, nodal or follicular lymphomas. Immunohistochemical, karyotypic, and genotypic studies have provided convincing proof that the supervening large-cell lymphomas arise from the same clone as the low-grade lymphomas [53]. Thus, the majority of high-grade lymphomas in SS patients may represent blastic-variance of either MZ B-cell or follicular center cell lymphomas.
SS patients with DLBCLs tend to be older than those with MALT lymphomas, with a median age at diagnosis of 58.4 versus 50.7 years respectively [6]. During transformation, the clinical picture is characterized by further nodal and extranodal dissemination [5]. The histologic transformation to high-grade lymphoma always denotes a poor prognosis. Consequently, it is crucial to identify de novo and secondary DLBCLs in SS patients since median overall survival is estimated at less than 2 years [5].
560 |
M. Voulgarelis and H.M. Moutsopoulos |
Fig. 37.7 Diffuse large B-cell lymphoma in Sjögren’s syndrome. Lymph node biopsy demonstrates a diffuse proliferation of large lymphoid cells that have totally effaced the architecture
37.3.2Treatment of DLBCL
Combined chemotherapy is recommended for patients with de novo or transformed DLBCL [50, 51]. A number of aggressive induction regimens have been used and evaluated in clinical studies, but large randomized trials have reported that the less aggressive classical CHOP chemotherapy (cyclophosphamide/doxorubicin/vincristine/prednisone) has comparable CR and overall survival rates. However, the median survival of SS patients with DLBCL treated with CHOP is estimated to be only 1.8 years [5]. The presence of B symptoms and a large tumor diameter (>7 cm) are independent death risk factors. In addition, CHOP therapy combined with an anti-CD20 monoclonal antibody (R-CHOP) has been shown to have a significant clinical effect in DLBCL among the general population, increasing both response rate and survival. These observations prompted us to use this regimen for the treatment of six SS patients with aggressive NHL [50, 51]. A major finding of our study was that R-CHOP induced sustained CR in all SS patients for a follow-up period of 2 years. Moreover, the extranodal manifestations of these patients, such as peripheral neuropathy and skin vasculitis, resolved after 8 cycles of R-CHOP. The remission of these symptoms and signs was accompanied by a decrease in the circulating mixed cryoglobulins as well as an increase in C4 complement component levels, indicating that this regimen effectively controls both the autoimmune and neoplastic process.
SS patients with unfavorable IPI score and involvement of more than one extranodal site are at a much higher risk of CNS disease, and should therefore be given CNS prophylaxis with intrathecal methotrexate injections [55]. Specific extranodal sites appear to be more frequently associated with CNS involvement, namely the testes, paranasal sinuses, hard palate, orbit, paravertebral masses, and bone marrow. Our observations warrant larger controlled trials to assess the effectiveness of this regimen.