Peripheral T-Cell Lymphoma of the Submandibular Salivary Gland as an Unusual Manifestation of Richter's Syndrome: A Case Report and Literature Review

Richter's syndrome is the development of high-grade non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In most patients with Richter's syndrome, the high-grade NHL is diffuse large B-cell lymphoma. Only a small minority of CLL/SLL patients develop T-cell malignancies. Herein, we describe a 40-year-old male patient presenting with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in the submandibular salivary gland, two years after the diagnosis of CLL/SLL. The PTCL-NOS consisted of small lymphocytes, which complicated diagnosis. Immunohistochemical, cytological, and molecular studies allowed the correct diagnosis of composite lymphoma (SLL/PTCL-NOS) of the submandibular salivary gland. The PTCL-NOS had a cytotoxic phenotype and aberrant expression of CD79a. There was no evidence to suggest that the PTCL-NOS of the submandibular salivary gland developed from an intimately associated submandibular lymph node or by PTCL-NOS dissemination. A review of the literature and presented case suppose that the PTCLs developed following CLL/SLL have the cytotoxic phenotype and can clinically mimic typical Richter's syndrome.


Introduction
Richter's syndrome is the development of high-grade non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) [1]. In most patients with Richter's syndrome, the high-grade NHL is di use large B-cell lymphoma. In rare cases, T-cell malignancies develop in patients with CLL/SLL. Single cases have been described of the combination of CLL/SLL and anaplastic large-cell lymphoma (ALCL) [2,3], T-cell large granular leukemia [4,5], subcutaneous panniculitis-like T-cell lymphoma [6], cutaneous gamma-delta T-cell lymphoma [7], mycosis fungoides [8], and peripheral T-cell lymphoma, not otherwise speci ed (PTCL-NOS) [8][9][10][11][12]. As some of the cases have been reported a while back [13][14][15][16][17], not all the peripheral T-cell lymphomas (PTCLs) have been subclassi ed as per the most recent World Health Organization Classi cation [18]. Herein, we describe an unusual manifestation of Richter's syndrome in the form of extranodal PTCL-NOS in the submandibular salivary gland.

Case Presentation
A previously healthy 38-year-old man presented with enlarged lymph nodes in the left supraclavicular and both axillary and inguinal areas. Computed tomography also revealed an increase of mediastinal, hilar, abdominal, retroperitoneal, retrocrural, and iliac lymph nodes, as well as hepatosplenomegaly. Peripheral blood ow cytometry showed 2095 B cells/mL with a CLL-like immunophenotype: CD19+, CD5+, CD23+, CD38+, CD79b−/CD43+, and CD22low/CD81low. Histology of an enlarged right axillary lymph node showed a distortion of the lymph node architecture by small lymphocytes expressing CD20, CD5, CD23, CD43, BCL2, and LEF1, consistent with SLL involvement. Peripheral blood mononuclear cells analyzed by FISH showed ATM (ataxia-telangiectasia mutated) gene deletion (11q23) in 25% of nuclei. A diagnosis of CLL/SLL stage II/B (Rai/Binet) was made. During the next two years, the disease remained stable and did not require any therapy. During a monitoring visit in March 2017, the patient noted the appearance of a dense painless mass in the left submandibular area, which rapidly increased in size within a month (Figure 1). e serum lactate dehydrogenase (LDH) level was elevated to 368 IU/L (normal < 225). Richter's syndrome was suspected. Ultrasound scanning and computed tomography did not allow categorical target organ identi cation (submandibular lymph node or submandibular salivary gland). Histologic examination revealed di use in ltration of the salivary gland tissue with small lymphocytes with atrophy of glandular parenchyma (Figure 2(a)). Immunohistochemical staining showed that only a part of the in ltration, mainly the focal cluster, was composed of lymphocytes expressing CD20 (Figure 2  of the focal cluster expressed the proliferative activity marker Ki-67 ( Figure 2(d)). e lymphoid in ltration consisted mostly of cells expressing CD2, CD3, CD5, CD7, CD8, CD43, TIA1, and granzyme B and coexpressing CD79a, with 70% Ki-67 positivity ( Figure 3). e study of imprints of the submandibular salivary gland showed two types of lymphocytes: one corresponding to CLL/SLL lymphocytes and the other with irregular nuclei and cytoplasmic granules ( Figure 4). Study of the DNA extracted from freshly prepared submandibular salivary gland tissue revealed clonal IGH and clonal TCRβ gene rearrangements ( Figure 5). A composite SLL/PTCL-NOS lymphoma of the submandibular salivary gland was diagnosed. Positron emission tomographycomputed tomography showed an increase in the size of the spleen, right submandibular, bilateral cervical, left supraclavicular and axillary, mediastinal, retrocrural, abdominal, retroperitoneal, and bilateral external iliac lymph nodes, with slightly increased accumulation of uorine-18 uorodeoxyglucose (SUV (standard uptake value) max 3.7) as well as an enlarged pericardial lymph node in the anterior mediastinum (SUVmax 6.1) ( Figure 6). e patient refused a diagnostic biopsy of the pericardial lymph node, bone marrow study, and therapy. Seven months after the diagnosis of extranodal PTCL-NOS, the patient feels well.

Discussion
Composite or discordant T-and B-cell lymphomas are uncommon, and T-cell lymphomas associated with CLL/SLL have been only rarely reported. A review of the literature shows 11 cases of CLL/SLL with PTCL-NOS (Table 1). In 6 cases, lymphomas were discordant (CLL/SLL and PTCL-NOS occurrence in separate anatomic sites), and in 5 cases, composite ones (CLL/SLL and PTCL-NOS occurrence in the same anatomical localization). In 4 cases, composite lymphoma was veri ed by biopsy of the lymph node, and in one case, by bone marrow biopsy. In all cases, CLL/SLL preceded PTCL-NOS, or both lymphomas were diagnosed simultaneously. In our case, SLL preceded the development of PTCL-NOS by 2 years. e rapid growth of an isolated mass in the submandibular region and increase of LDH suggested the development of Richter's syndrome. Histology revealed that the lesion was localized in the submandibular salivary gland. Di use in ltration of submandibular salivary gland     [8] 58/F ND NA + + -+ (LN) Campidelli et al. [9] 80/M − − + + -+ (LN) Campidelli et al. [9] 61/M − − ND + -+ (BM) Buddula and Assad [10] 66/M 72 + (PCT) + + + -Alomari et al. [11] 68/F 84 + (PCT/RT) − + -+ (LN) Boyer et al. [12] 70 Unlike other reports that have described a composite SLL and PTCL-NOS lymphoma [8,9,11], in our case, PTCL consisted of small lymphocytes, which precluded histological veri cation. e discrepancy in the clinical picture (rapid growth of the tumor) and the unspeci c histological picture prompted us to conduct further studies. Immunohistochemistry showed a cytotoxic (CD8+, TIA1+, and granzyme B+) T-cell in ltrate with high proliferative activity (70% Ki-67 positivity), with in ltrating B-lymphocytes foci of CLL/SLL immunophenotype showing signi cantly less proliferative activity (20% Ki-67 positivity). Molecular analysis detected monoclonal rearrangement of the IGH and TCRβ genes in the in ltrating cells. Cytological study of imprints of the submandibular salivary gland revealed two di erent lymphoid populations.
us, a combination of immunohistochemistry, molecular, and cytological studies allowed the diagnosis of composite SLL/PTCL-NOS lymphoma of the submandibular salivary gland. e two lymphomas in the submandibular salivary gland were not clearly delineated, which made it di cult to assess their immunophenotype. Nevertheless, a careful evaluation of the immunohistochemical picture of the composite lymphoma uncovered the aberrant expression of CD79a by T cells of PTCL-NOS. Literature shows 7 cases of peripheral T-cell lymphomas with aberrant CD79a expression [19][20][21][22] (Table 2), and in all 6 cases where the expression of cytotoxic molecules was evaluated, tumor T cells had a cytotoxic phenotype. In addition, 5 out of 7 cases were extranodal lymphomas.
Salivary gland lymphomas account for approximately 5% of all extranodal lymphomas [23], 1% to 2% of all salivary gland neoplasms [24], and about 10% of all salivary gland malignancies [25]. Lymphomas of the salivary glands are biologically heterogeneous and inevitably include genuine extranodal lymphomas and nodal-type lymphomas, with the latter arising in intrasalivary lymph nodes [26]. It can be di cult to distinguish between the two types because the lymphoma cells often spill over into the adjacent tissues. e de nition of a true primary salivary gland lymphoma is an issue. Schmid et al. reported that if a lesion has no capsulelike structure reminiscent of an expanded lymph node capsule and no lymph nodes, it can be de ned as a true primary salivary gland lymphoma [27]. e majority of salivary gland lymphomas are of B-cell lineage. In contrast, primary salivary gland T-cell and NK-cell lymphomas are extremely rare. To the best of our knowledge, only 16 such cases have been reported [28][29][30][31][32][33][34]. Nine cases were parotid salivary gland lymphomas (one case with intrasalivary gland lymph nodal origin), 5 were submandibular salivary gland lymphomas, and 2 were sublingual salivary gland lymphomas. Histological subtypes were variable and included PTCL-NOS, ALCL, NK-cell lymphoma, and adult T-cell lymphoma/leukemia. In our case, there was no evidence to suggest that the PTCL-NOS of the submandibular salivary gland developed from an intimately associated submandibular lymph node or PTCL-NOS dissemination. e pathogenesis of PTCL-NOS lymphoma arising in association with CLL/SLL is not well understood, and several hypotheses may be conceived. It is intriguing that all cases of PTCL-NOS reported in CLL/SLL patients expressed cytotoxic granule proteins (Table 1, except one case where data were unavailable), in contrast to T-cell lymphomas in the general population [35,36]. In our case, the PTCL-NOS also expressed cytotoxic proteins: TIA1 and granzyme B.
Cytotoxic T-cell lymphomas are often associated with chronic antigenic stimulation or chronic immunosuppression [37]. e decreased immunosurveillance accompanying CLL/SLL is well documented, and studies of cellular immunity in CLL/SLL patients have found reduced T-cell function with a paradoxical clonal expansion of CD8+ T cells [8] and increased circulating CD8+ T-cell counts [38].
eoretically, this could increase the incidence of T-cell large granular leukemia in CLL/SLL patients, but only 2 cases of such an association are described in the literature [4,5]. e second possibility is the exposure to chemotherapy for CLL/SLL that induces a secondary neoplasm. Information on CLL/SLL therapy before the development of PTCL-NOS was provided for only 7 of 11 patients (Table 1). Four patients received multiagent chemotherapy including udarabine, one patient received experimental therapy with interleukin 4, and in 2 patients, therapy was not administered (since both lymphomas were diagnosed simultaneously). In our patient, before development of PTCL-NOS, the CLL/SLL therapy was not indicated [39], and we adhered to the wait-and-watch approach.
e assumption is supported by the PET-CT. However, we cannot de nitively interpret the enlarged pericardial lymph node in the anterior mediastinum with the SUVmax 6.1. Such an SUV can be observed in the lymph node lesion by both SLL [40] and PTCL as well [41].
We believe this is the rst reported case of composite lymphoma (SLL/PTCL-NOS) of the submandibular salivary gland. A feature of this case was the absence of histological signs, indicating the presence of a second lymphoma in the salivary gland initially a ected by SLL. e PTCL-NOS consisted of small lymphocytes with a cytotoxic phenotype and aberrant CD79a expression.
Data Access e datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethical Approval
is study was reviewed and approved by the V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences Institutional Review Board.

Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflicts of Interest
e authors declare that they have no con icts of interest.