Vol. 131 No. 1 January 2021

Richter transformati

on in the oral and maxillofacial area:report of 2 cases and literature review Vasileios Ionas Theofilou, DDS, MSc Student,a Nikolaos Katsoulas, MD, DDS, MSc,b

Konstantinos I. Tosios, DDS, PhD,c Alexandra Sklavounou, DDS, MSc, PhD,d and

Nikolaos G. Nikitakis, MD, DDS, PhDe

Richter transformation (RT) is a term used to refer to the development of an aggressive lymphoma, usually of diffuse large B-cell

lymphoma type, in a patient with a history of chronic lymphocytic leukemia. It may present with heterogeneous manifestations,

including the occurrence of tumors at extranodal sites. To date, only 6 cases of RT involving the oral and maxillofacial region

have been reported. Here, we present 2 rare cases of lymphoma initially affecting the maxilla and the lower gingiva, respectively,

of female patients with chronic lymphocytic leukemia and review the English language literature about RT manifesting in the oral

and maxillofacial tissues. (Oral Surg Oral Med Oral Pathol Oral Radiol 2021;131:e14�e20)

The term Richter transformation (RT) or Richter

syndrome describes the development of an aggressive

lymphoma in a patient with chronic lymphocytic leuke-

mia (CLL). This is usually a non-Hodgkin lymphoma

(NHL), more commonly a diffuse large B-cell lym-

phoma (DLBCL)1,2 and rarely Hodgkin lymphoma

(HL-Richter),3 or another aggressive lymphoid malig-

nancy, such as composite lymphoma,4 dendritic cell

sarcoma,5 or plasmablastic lymphoma.6 Multiple mye-

loma may also develop in patients with CLL, although

it is controversial whether this is coincidental or repre-

sents a Richter-like phenomenon.7

The prevalence of RT among patients with CLL

varies from 0.7% to 23%.8 In a prospective cohort

study,1 in approximately 2% of patients with CLL,

DLBCL developed in 5 years, whereas the 10-year

incidence of RT has ranged from 4.9%1 to 16.2%.9

RT is more common in males and median age is

greater than 60 years.1,2 Predisposing factors include

advanced-stage CLL1,9; lymph nodes 3 cm or greater9;

expression by neoplastic cells of proteins ZAP70,1,9

CD38,1,9 or CD49d1; nonmutated immunoglobulin

heavy-chain variable region gene (IGHV)1; IGHV4-39

usage9; absence of del (13q14)9 and presence of del

aDepartment of Oral Medicine and Pathology, Faculty of Dentistry,

National and Kapodistrian University of Athens, Athens, Greece.bDepartment of Oral Medicine and Pathology, Faculty of Dentistry,

National and Kapodistrian University of Athens, Athens, Greece.cAssociate Professor, Department of Oral Medicine and Pathology,

Faculty of Dentistry, National and Kapodistrian University of

Athens, Athens, Greece.dProfessor, Department of Oral Medicine and Pathology, Faculty of

Dentistry, National and Kapodistrian University of Athens, Athens,

Greece.eProfessor and Chair, Department of Oral Medicine and Pathology,

Faculty of Dentistry, National and Kapodistrian University of

Athens, Athens, Greece.

Received for publication Nov 24, 2019; returned for revision Jan 16,

2020; accepted for publication Feb 17, 2020.

� 2020 Elsevier Inc. All rights reserved.

2212-4403/$-see front matter

https://doi.org/10.1016/j.oooo.2020.02.016

e14

(11q22.3) or del (17p13)1; and prior treatment for

CLL.1

We report here 2 cases of CLL in which DLBCL

developed in the oral cavity and review the literature

on oral and maxillofacial involvement by RT.

CASE REPORTSCase 1An 82-year-old female was referred by her dentist for

evaluation of “poor soft tissue healing following periodon-

tal scaling.” Five years earlier, the patient had been diag-

nosed with CLL stage I that did not necessitate any kind

of treatment, and she was under regular follow-up by her

hematologist. Complete blood count a month before pre-

sentation to us showed lymphocytosis (76%; normal range

18%�44%) and increased lactate dehydrogenase (LDH;

326 units/L; normal range 122�214 units/L), as well as

normocytic anemia (red blood cell [RBC] count

3,620,000/mL; normal range 4,200,000�5,400,000/mL;hematocrit [Hct] 35%; normal range 36%�46%; hemo-

globin [Hgb] 11.4 g/100 mL; normal range 12�16 g/100

mL; mean corpuscular volume [MCV] 97 fL; normal

range 77�98 fL); and neutropenia (13%; normal range

35%�80%). These findings were considered consistent

with the underlying disease by her attending hematologist.

She was treated for rheumatoid arthritis with hydroxy-

chloroquine and for chronic atrophic gastritis with

monthly injections of B12. Her medical history also

included hyperthyroidism, hypertension, and osteoporosis

that were not being treated.

Clinical examination showed that the patient was

edentulous, except for 4 teeth in the anterior mandible

(Figure 1). The gingiva surrounding those teeth were

enlarged, erythematous, and ulcerated. The rest of the

oral mucosa was within normal limits. A panoramic

radiograph showed limited alveolar bone loss around

teeth, consistent with chronic periodontitis.

Because of the history of CLL, infiltration of the gingiva

by the hematologic malignancy was suspected, and inci-

sional biopsy was performed. Microscopic examination

Fig. 1. Patient 1. Diffuse gingival enlargement affecting the

anterior mandibular gingiva.

OOOO CASE REPORT

Volume 131, Number 1 Theofilou et al. e15

showed diffuse infiltration by small cells with morphologic

characteristics of lymphocytes, mostly in the superficial

lamina propria (Figure 2A), and large atypical mononucle-

ated or binucleated cells with anaplastic characteristics in

the deeper locations (Figure 2B). Abundant mitoses were

also present. After a provisional hematoxylin and

eosin�based diagnosis of lymphoproliferative lesion, fur-

ther examination of the biopsy tissue was performed by an

expert hematopathologist. Immunohistochemically, the

small cells were CD20+, CD79a+, CD5+, OCT+,

CD23�, CD30�, CD15�, CD3�, and multiple myeloma

oncogene (MUM)�, whereas in situ hybridization for

Epstein-Barr virus (EBV)�encoded RNA was negative.

The large cells were CD20+ and CD79a+ (in equal num-

bers), CD23+, CD30+>>CD15+, OCT+, MUM+, CD5-,

Fig. 2. Patient 1. Microscopic examination shows (A) small cells with

location and (B, C) large pleomorphic cells with anaplastic features

magnification£ 400). A high-resolution version of this slide for use wit

CD3-, whereas EBV�encoded RNA was positive. Poly-

merase chain reaction was performed for

the identification of immunoglobulin heavy-chain

(IGVH) gene mutational status and proved a clonal

relationship between the underlying and the present

hematologic malignancy. The final diagnosis was

gingival infiltration by a CD5+, CD23� B-cell lym-

phoproliferative lesion with small lymphocytic fea-

tures, consistent with CLL, with transformation to a

diffuse high grade EBV(+) B-cell lymphoma com-

posed of large anaplastic CD30+>>CD15+ cells, in

the context of Richter syndrome.

The patient was treated with 6 cycles of chemother-

apy with rituximab (500 mg), cyclophosphamide (1000

mg), vincristine (1.8 mg), and prednisolone (75 mg), as

well as 30 cycles of radiotherapy (total dose 30 Gy).

However, she was lost to follow-up.

Case 2A 70-year-old female presented for the evaluation and

management of a painless mass in the upper lip.

According to her account, it had been first noticed

approximately 3 years earlier, but in the past 3 weeks,

it had enlarged and excreted pus-like material. Her den-

tist had ruled out a dental or periodontal origin. Her

medical history was significant for CLL stage I, diag-

nosed approximately 8 years earlier. She had not

received any treatment for CLL and was under regular

follow-up by her attending hematologist. Blood tests

phenotypic characteristics of lymphocytes in a more superficial

in the deep lamina propria (hematoxylin and eosin stain; initial

h the Virtual Microscope is available as eSlide: VM05760.

Fig. 3. Patient 2. Large mass in the anterior maxilla projec-

ting to the (A) sulcus and (B) palate.

Fig. 4. Patient 2. Three-dimensional (3-D) reconstruction of

the cone beam computed tomography scan shows a hypo-

dense lesion causing perforation of the buccal and palatal cor-

tical plates and extending to the floor of the nasal cavity.

ORAL ANDMAXILLOFACIAL PATHOLOGY OOOO

e16 Theofilou et al. January 2021

during this period showed CLL-associated leukocytosis

and anemia managed with folic acid per os. LDH was

within normal limits (377 units/L; normal range

230�460). The patient was also being treated for

hypertension with amlodipine besylate, hypothyroid-

ism with levothyroxine sodium, and osteopenia with

risedronate sodium.

Clinical examination revealed a tumor in the middle

of the maxilla and extending to the sulcus and the pal-

ate (Figures 3A and 3B). The tumor was covered by

normal-appearing mucosa and was soft to fluctuant and

painless on palpation. The involved teeth showed class

II mobility. The rest of the oral mucosa was within nor-

mal limits. Cone beam computed tomography showed

an ill-defined soft tissue density lesion in the anterior

region of the maxilla, measuring approximately

3.5 £ 3.0 £ 2.5 cm, causing perforation of both the

frontal and palatal cortical plates and extending to the

floor of the nasal cavity (Figure 4).

Incisional biopsy was performed with the patient under

local anesthesia, and histopathologic examination showed

diffuse infiltration by large atypical neoplastic cells

(Figure 5) with pleomorphic grooved nuclei and indistinct

nucleoli. Mitoses, some of them atypical, were also

detected. Additionally, small cells with phenotypic charac-

teristics consistent with lymphocytes were distinguished

focally, mostly in perivascular and perineural localization.

Crush artifacts were observed. These features were consis-

tent with NHL, and after further investigation by an expert

hematopathologist, the immunoprofile of the tumor was

shown to be positive for CD20, CD79a, bcl2, bcl6, CD23,

and CD30 and negative for c-myc, CD10, MUM-1, CD5,

and CD138; the Ki67 index was 80% to 90%. Based on

the histologic and immunohistochemical examination, the

diagnosis was diffuse large B-cell lymphoma with features

not otherwise specified, probably originating from the ger-

minal center.

A full workup of the patient was undertaken, but no

significant findings were revealed on chest and abdomi-

nal CT scans, the imaging features being similar to the

latest evaluation performed 3 years ago.

The patient underwent 8 cycles of treatment with carfil-

zomib. Five months after commencement of therapy, her

clinical condition and laboratory findings were satisfac-

tory, and the maxillary lesion had regressed completely

(Figure 6). Twenty-one months later no sign of recurrence

was present.

DISCUSSIONWe reported here 2 cases of DLBCL developing in the

oral cavity of patients with CLL, which conformed to the

diagnosis of RT.2 An English language literature review

disclosed 6 previously reported cases of oral and maxillo-

facial RT,10-15 whose main features, along with those of

the present cases, are summarized in Table I. Mean age

was 65.1 years, and females were more commonly

affected compared with males (female/male ratio 6:2).

The latter finding is in contrast to the more common find-

ing of more involvement in males by both RT1,2 and oral

and maxillofacial lymphomas.16

DLBCL, the most frequently encountered type of

NHL in the oral and maxillofacial area16 and the most

common lymphoma in RT,1,2 was diagnosed in the

Fig. 5. A, B, Patient 2. Diffuse proliferation by large atypical

basophilic cells with occasional mitoses, intermixed with

smaller cells with morphologic features of lymphocytes

(hematoxylin and eosin stain; initial magnification £ 400). A

high-resolution version of this slide for use with the Virtual

Microscope is available as eSlide: VM05761.

OOOO CASE REPORT

Volume 131, Number 1 Theofilou et al. e17

majority of cases (6 patients), whereas in 2 patients, the

diagnosis was plasmablastic lymphoma. Mean time

between diagnosis of CLL and development of RT was

approximately 5 years. The jaws were the most com-

mon site of involvement, with 6 of 8 cases (2 cases in

the maxilla, 2 in the mandible, 1 with simultaneous

involvement of both jaws, and 1 in an unspecified jaw),

followed by the gingiva and the cheek, with 1 case

each. This distribution is in agreement with the com-

mon and equal involvement of both jaws by NHL.16,17

Lymphomas in RT are, in most cases, clonally related to

the pre-existing CLL directly—that is, lymphoma cells

Fig. 6. Patient 2. Complete response of the maxillary lesion 5

months after initiation of chemotherapy.

derive from the original CLL clone (linear evolution); or

indirectly, both CLL and lymphoma cells derive from a

common precursor cell (branching evolution).18 Clonal

relationship should be established by IGHV-D-J rearrange-

ment analysis.8,19 This is considered essential because of

differences in the therapeutic management of clonally

related and clonally unrelated RT, with the latter being

treated in a similar fashion to de novo DLBCL.8,19 A clonal

relationship between CLL and lymphoma was proved in

one of our cases (case 1) and in that of Evans et al.14

In approximately 20% of NHL developing in

patients with CLL, a clonal relationship cannot be

established.20 In those cases, the biologic features and

prognoses are more comparable with those of conven-

tional NHL; therefore, they are considered to be de

novo malignanicies.8

Even though the exact molecular mechanisms of RT

have not been fully elucidated, there are reports of genetic

alterations in CLL cells that cause transformation to the

clonally related lymphoma. Approximately 90% of RT

cases exhibit genetic lesions in pathways that cause disrup-

tion of general cell regulators, such as tumor suppression,

cell cycle, and cell proliferation (e.g., TP53, NOTCH1,

MYC, and CDKN2A).18 Those genetic lesions are associ-

ated with the aggressive clinical behavior resulting from

acquired features—resistance to chemotherapy and rapid

disease progression.18

Previous therapy has also been suggested as a risk

factor for the development of RT, although a mecha-

nism has not been described.1 From another point of

view, CLL requiring chemotherapy is usually an

aggressive disease with poor biologic behavior, where

the risk for the development of a lymphoma is, never-

theless, high.1 We reported for the first time 2 cases

where RT developed in the oral cavity of patients with

no previous treatment for CLL because in the previ-

ously reported 6 cases, different types of chemothera-

peutic regimens had been applied.

RT in CLL-untreated patients is rarely EBV related,

whereas in patients in immunosuppressive therapy, it is

suggested that EBV reactivation may drive the devel-

opment of the aggressive lymphoma.21 One of the

cases presented here (case 1) is the first EBV-positive,

clonally related oral RT in a previously untreated

patient with CLL. Although the EBV status of the

patient before RT was not known, it may be hypothe-

sized that in this case, a secondary EBV infection drove

the lymphomatogenesis.

Diagnosis of RT is based on clinical and pathologic

examinations, as well as imaging. Severe deterioration

in a patient with CLL manifesting fever, rapid lymph-

adenopathy, extranodal involvement presenting with

tumors mostly of the gastrointestinal tract or bones,

severe weight loss, hypercalcemia, and markedly ele-

vated LDH are features that could raise the suspicion

Table I. Cases of Richter transformation with manifestations in the oral cavity or the jaws

Year Authors Age Gender Type of

lymphoma

Time

to RT

Site of

involvement

Other manifestations Clonal

relationship

Prior treatment Treatment for RT Follow-up

1980 Trump

et al.

66 F DLBCL 7 Maxilla Swollen ankles, wrist and

knee, axillary adenopathy

and hepatosplenomegaly

NI Chlorambucil Radiotherapy, CVP, BABV 8 months DOD

1983 Kendrick

et al.

77 F DLBCL 4, 5 Buccal area Fever, liver and spleen

enlargement

NI Chlorambucil,

radiotherapy

CHO 6 months DOD

2001 Robak et al. 61 F PL 4 Mandible Peripheral paresis of facial

nerve

NI 2-CdA, prednisone VAD, CHOP 6 months DOD

2013 Wi�sniewska-Piaty et al.

NM F DLBCL NM Mandible Confusion, hypercalcemia,

diplopia, ptosis as well as

lytic lesions in the skull,

humerus, scapula and ribs

NI CC, R-CHOP, R-ESHAP,

FMD, RB, radiotherapy

CHOP DOD (unknown

follow-up)

2015 Evans et al. 62 M PL (from

DLBCL)

4 Jaw

(unspecified)

Lymphadenopathy Yes FCR, BR, ofatumumab,

CHOP, flavopiridiol and

lenalinomide, ibrutinib

OFAR, XPO1, CTL019

(before PL) Radiotherapy

(after PL development)

1 month DOC

2017 Bezinelli

et al.

38 M DLBCL 2 Maxilla and

mandible

Lymphadenopathy, lytic

lesions in the skull and

ileac bone

NI R-CHOP, FCR, AHSCT R-ESHAP, methotrexate,

cytarabine, dexamethasone

5 months CR

Current

case 1

82 F DLBCL 5 Mandibular

gingiva

None Yes No Radiotherapy, R-COP Lost to follow-up

Current

case 2

70 F DLBCL 8 Maxilla None NI No Carfilzomib 26 months CR

2-CdA, cladribine; AHSCT, allogeneic hematopoietic stem cell transplantation; BABV, bleomycin, adriamycin, vinblastine, and l-3-bis (2-chloroethyl- 1-nitrosourea); BR, bendamustine and rituximab; CC,

cyclophosphamide and cladribine; CHO, cyclophosphamide, doxorubicin, and vincristine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, Complete response; CTL019, chimeric

antigen receptor�modified T cells targeted for CD19; CVP, cyclophosphamide, vincristine, and prednisone; DLBCL, diffuse large B-cell lymphoma; DOC, died of complications; DOD, died of disease; F,

female; FCR, fludarabine, cyclophosphamide, and rituximab; FMD, fludarabine, mitoxantrone, and dexamethasone; M, male; NI, not investigated; NM, not mentioned; OFAR, oxaliplatin, fludarabine, cytar-

abine, and rituximab; PL, plasmablastic lymphoma; RB, rituximab and bendamustine; R-CHOP, rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone; R-COP, rituximab, cyclophospha-

mide, vincristine, and prednisolone; R-ESHAP, rituximab, etoposide, cisplatin, cytarabine, and methylprednisolone; RT, Richter transformation; VAD, vincristine, doxorubicin, and dexamethasone; XPO1,

inhibitor of exportin 1.

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FACIALPATHOLO

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OOOO CASE REPORT

Volume 131, Number 1 Theofilou et al. e19

of RT development.8,19 In both cases presented here,

the patients did not have any signs or symptoms other

than swelling in the oral cavity. The most common

signs in previously reported cases of oral and maxillo-

facial RT (see Table I) were lymphadenopathy in 3

cases, followed by hepatosplenomegaly and lytic

lesions in bones other than the jaws in 2 cases each.

Histopathologic examination most commonly

reveals diffuse infiltration by large atypical cells exhib-

iting pleomorphism and a centroblastic morphology.20

They are CD20 positive, with the markers CD5 and

CD23 suggestive of CLL being expressed in 32% and

14%, respectively.20 RT cases most commonly show a

nongerminal phenotype, whereas germinal center B-

cell type DLBCL cases are rarer.20,22

When RT is suspected in the absence of clinically

evident nodal or extranodal masses, imaging with F-18

fluorodeoxyglucose positron emission tomography is

the diagnostic procedure of choice.8,19 The characteris-

tics of the lesions detected, along with the standardized

uptake value, exhibit a significant sensitivity and indi-

cate whether biopsy should be performed, facilitating

the diagnosis of RT.8

RT treatment is challenging. Immunochemotherapy,

stem cell transplantation, and novel targeted therapeutic

agents have been tested with varying results with regard to

patients’ response and overall survival.8. DLBCL in

patients with RT acquires significant resistance to chemo-

therapy.8 Some of the chemotherapeutic regimens exhibit

a low complete response rate (7%), with higher overall

survival (21 months) and low treatment-induced mortality

(5%),23 whereas others show a better response (complete

response 38%) with a lower overall survival (10 months)

because of the high toxicity of the chemotherapeutic

agents.24 Allogenic and autologous stem cell transplanta-

tions have been used. Overall 3-year survival of patients

receiving allogenic stem cell transplantation and autolo-

gous stem cell transplantation is 36% and 59%, respec-

tively, as indicated by a retrospective analysis.25 However,

in most cases, stem cell transplantation is not an option

because patients are unfit, either because of their age or

because of insufficient response to initial chemotherapeutic

treatment.25 Novel agents that target the molecular path-

ways deregulated in patients with RT include the Bruton

tyrosine kinase inhibitor ibrutinib, the B-cell lymphoma 2

antagonist venetoclax, the programmed cell death protein

1 antagonist pembrolizumab, and the exportin 1 inhibitor

selexinor. The overall response rate varies from 33% for

selexinor26 to 75% for ibrutinib,27 but the number of cases

studied is too limited for any conclusions to be reached.

Of the 8 cases presented in Table I, different immuno- or

chemotherapeutic regimens were applied in 5 cases, com-

bination of chemotherapy with radiation therapy in 2 cases,

solely radiation in 1 case.

The median survival of patients with CLL with RT is

approximately 2 years,1 with clonally unrelated cases

exhibiting a behavior similar to that of de novo DLBCL,

whereas clonally related cases have a significantly lower

survival rate. Additional factors diminishing overall sur-

vival are LDH levels greater than 1.5 times the normal,28

tumor size greater than 5 cm,28 platelet count less than

100 £ 109/L,28 number of prior therapies greater than

1,28 Zubrod score greater than 1,21,28 TP53 deletions or

mutations,19 and poor response to RT treatment.19 Five of

the patients with oral and maxillofacial RT died either as

a result of the spread of the lymphoma or because of che-

motherapeutic toxicity, at a mean period of approxi-

mately 5 months, and 2 patients showed signs of

remission at the 5-month follow-up.

CONCLUSIONSAlthough first presentation of RT in the oral and maxil-

lofacial area is extremely rare, clinicians should have a

high level of suspicion when dealing with patients with

CLL showing atypical lesions in the area because these

lesions could be manifestations of an underlying RT.

ACKNOWLEDGMENTSWe are grateful for the expert assistance of Ms. Maria

Manou, technician.

REFERENCES1. Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lym-

phoma (Richter syndrome) in patients with chronic lymphocytic

leukaemia (CLL): a cohort study of newly diagnosed patients.

Br J Haematol. 2013;162:774-782.

2. Tadmor T, Shvidel L, Bairey O, et al. Richter’s transformation to

diffuse large B-cell lymphoma: a retrospective study reporting

clinical data, outcome, and the benefit of adding rituximab to

chemotherapy, from the Israeli CLL Study Group. Am J Hema-

tol. 2014;89:E218-E222.

3. Parikh SA, Habermann TM, Chaffee KG, et al. Hodgkin trans-

formation of chronic lymphocytic leukemia: incidence, out-

comes, and comparison to de novo Hodgkin lymphoma. Am J

Hematol. 2015;90:334-338.

4. Michelis FV, Kourti G, Skertsou M, Karmiris T, Rontogianni DP,

Harhalakis N. Richter transformation of chronic lymphocytic leu-

kemia into composite diffuse large B-cell and Hodgkin lym-

phoma. Leuk Lymphoma. 2012;53:2302-2303.

5. Fraser CR, Wang W, Gomez M, et al. Transformation of chronic

lymphocytic leukemia/small lymphocytic lymphoma to interdig-

itating dendritic cell sarcoma evidence for transdifferentiation of

the lymphoma clone. Am J Clin Pathol. 2009;132:928-939.

6. Martinez D, Valera A, Perez NS, et al. Plasmablastic transforma-

tion of low-grade b-cell lymphomas: report on 6 cases. Am J

Surg Pathol. 2013;37:272-281.

7. Alley CL, Wang E, Dunphy CH, et al. Diagnostic and clinical

considerations in concomitant bone marrow involvement by

plasma cell myeloma and chronic lymphocytic leukemia/mono-

clonal B-Cell lymphocytosis: a series of 15 cases and review of

literature. Arch Pathol Lab Med. 2013;137:503-517.

8. Rossi D, Gaidano G. Richter syndrome: pathogenesis and man-

agement. Semin Oncol. 2016;43:311-319.

ORAL ANDMAXILLOFACIAL PATHOLOGY OOOO

e20 Theofilou et al. January 2021

9. Rossi D, Cerri M, Capello D, et al. Biological and clinical risk

factors of chronic lymphocytic leukaemia transformation to

Richter syndrome. Br J Haematol. 2008;142:202-215.

10. Trump DL, Mann RB, Phelps R, Roberts H, Conley CL.

Richter’s syndrome: diffuse histiocytic lymphoma in patients

with chronic lymphocytic leukemia. A report of five cases and

review of the literature. Am J Med. 1980;68:539-548.

11. Kendrick RW, Schwartz HC. Richter’s syndrome presenting as a

facial swelling. Oral Surg Oral Med Oral Pathol. 1983;56:301-304.

12. Robak T, Urba�nska-Ry�s H, Strzelecka B, et al. Plasmablastic

lymphoma in a patient with chronic lymphocytic leukemia

heavily pretreated with cladribine (2-CDA): an unusual variant

of Richter’s syndrome. Eur J Haematol. 2001;67:322-327.

13. Wi�sniewska-Piaty K, Helbig G, Wo�zniczka K, Frankiewicz A,

Dziaczkowska-Suszek J, Kyrcz-Krzemie�n S. Richter’s syndrome

manifested as diffuse large B-cell lymphoma of the mandible

with lytic lesions and hypercalcemic crisis. Acta Haematol Pol.

2013;44:409-412.

14. Evans AG, Rothberg PG, Burack WR, et al. Evolution to plas-

mablastic lymphoma evades CD19-directed chimeric antigen

receptor T cells. Br J Haematol. 2015;171:205-209.

15. Bezinelli LM, de Paula Eduardo F, Marques da Graca Lopes R,

Pasqualin D da C, Hamerschlak N, Correa L. Tumor mass in the

palate after bone marrow transplantation. Oral Surg Oral Med

Oral Pathol Oral Radiol. 2017;124:107-113.

16. Guevara Canales JO, Morales Vadillo R, de Faria PEA, Sacsa-

quispe Contreras SJ, Leite FPP, Chavez MGMA. Systematic

review of lymphoma in oral cavity and maxillofacial region.

Acta Odontol Latinoam. 2011;24:245-251.

17. Matsuzaki H, Katase N, Hara M, et al. Primary extranodal lym-

phoma of the maxilla: a case report with imaging features and

dynamic data analysis of magnetic resonance imaging. Oral Surg

Oral Med Oral Pathol Oral Radiol Endod. 2011;112:e59-e69.

18. Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions asso-

ciated with chronic lymphocytic leukemia transformation to

Richter syndrome. J Exp Med. 2013;210:2273-2288.

19. Khan M, Siddiqi R, Thompson PA. Approach to Richter trans-

formation of chronic lymphocytic leukemia in the era of novel

therapies. Ann Hematol. 2018;97:1-15.

20. Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH muta-

tional status and clonality analysis of Richterʼs transformation.

Am J Surg Pathol. 2007;31:1605-1614.

21. Garc�ıa-Barchino MJ, Sarasquete ME, Panizo C, et al. Richter

transformation driven by Epstein-Barr virus reactivation during

therapy-related immunosuppression in chronic lymphocytic leu-

kaemia. J Pathol. 2018;245:61-73.

22. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter

syndrome reveals disease heterogeneity and predicts survival

after transformation. Blood. 2011;117:3391-3401.

23. Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolera-

bility of R-CHOP in relapsed/refractory chronic lymphocytic leuke-

mia and Richter transformation. Am J Hematol. 2014;89:E239-E243.

24. Dabaja BS, O’Brien SM, Kantarjian HM, et al. Fractionated

cyclophosphamide, vincristine, liposomal daunorubicin (dau-

noxome), and dexamethasone (hyperCVXD) regimen in

Richter’s syndrome. Leuk Lymphoma. 2001;42:329-337.

25. Cwynarski K, van Biezen A, de Wreede L, et al. Autologous and

allogeneic stem-cell transplantation for transformed chronic

lymphocytic leukemia (Richter’s syndrome): a retrospective

analysis from the chronic lymphocytic leukemia subcommittee

of the chronic leukemia working party and lymphoma working

party of the European Group for Blood and Marrow Transplanta-

tion. J Clin Oncol. 2012;30:2211-2217.

26. Kuruvilla J, Savona M, Baz R, et al. Selective inhibition of

nuclear export with selinexor in patients with non-Hodgkin’s

lymphoma. Blood. 2017;129:3175-3183.

27. Tsang M, Shanafelt TD, Call TG, et al. The efficacy of ibrutinib in

the treatment of Richter syndrome. Blood. 2015;125:1676-1678.

28. Tsimberidou AM, O’Brien S, Khouri I, et al. Clinical outcomes and

prognostic factors in patients with Richter’s syndrome treated with

chemotherapy or chemoimmunotherapy with or without stem-cell

transplantation. J Clin Oncol. 2006;24:2343-2351.

Reprint requests:

Vasileios I. Theofilou

Department of Oral Medicine and Pathology

Faculty of Dentistry

2 Thivon Street

11526 Athens

Greece.

vasilistheofilou@gmail.com