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Gynecologic Oncology

Case Report

Primary ovarian large B-cell lymphoma in patient with juvenile

rheumatoid arthritis treated with low dose Methotrexate

Yusuf Yildirim

Department of Gynecologic Oncology, SSK Agean Obstetric and Gynecology Teaching Hospital,

Department of Gynecologic Oncology, Yenisehir, Izmir, Turkey

Received 14 July 2004

Available online 2 February 2005

Abstract

Background. Primary ovarian lymphoma is an extremely rare disease and limited count reports about it have been reported in the

literature. Traditionally, patients with rheumatoid arthritis (RA) have increased risk of nodal and extranodal lymphoid malignancies such as

non-Hodgkin’s lymphoma (NHL). Recently, some studies have also reported association between patients with juvenile rheumatoid arthritis

(JRA) treated with Methotrexate (MTX) and malignant lymphoma developing.

Case. We report a 17-year old JRA patient with primary ovarian diffuse large B-cell non-Hodgkin’s lymphoma (NHL). The patient had

seronegative (rheumatoid factor negative) poliarticular form of JRA and was receiving low dose weekly Methotrexate (MTX) during the past

2 years. Initial presentation was adnexial mass and chronic pelvic pain. The patient was treated with surgery and combined cytotoxic

chemotherapy.

Conclusion. In conclusion, because of increased lymphoid malignancy risk, ovarian masses in JRA patients should be carefully evaluated.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Juvenile rheumatoid arthritis; Methotrexate; Primary ovarian lymphoma

Introduction

Malignant lymphoma affecting the ovary can be divided

into two types; primary and disseminated [1]. Primary

ovarian non-Hodgkin’s lymphoma (NHL) is an extremely

rare disease as other primary lymphomas of the genital tract,

accounting for 0.5% of all NHL and 1.5% of all malignant

ovarian neoplasms. It generally has B-cell phenotype,

unilateral occurrence, and intermediate-grade [2].

It is considered that primary ovarian NHL arises from

hilar lymphoid tissue or teratoma in the ovary. However, if

stringent criteria are used for case selection, true primary

ovarian NHL is very rare than ovarian involvement due to

systemic nodal disease. Fox et al. have suggested three

criteria for the diagnosis of primary ovarian lymphoma.

These are the following: (1) tumor has confined to the ovary

0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ygyno.2004.12.035

E-mail address: Ykuzeyli@mynet.com.

regional lymph nodes or adjunctive organs at the time of the

diagnosis, (2) bone marrow and peripheral blood has not

contained any abnormal cells, and (3) if extra-ovarian

disease occurred later, there must be a few months between

the time of ovarian and extra-ovarian lesions [3].

Juvenile rheumatoid arthritis (JRA) is a variation of

rheumatoid arthritis (RA) occurring during childhood and a

heterogeneous group of autoimmune disease resulting in

chronic idiopathic peripheral arthritis. The etiology of JRA

is unclear, and its treatment is ameliorative rather than

curative. Among pharmacologic agents, Methotrexate

(MTX) which is termed disease-modifying antirheumatic

drug has proven to be the most effective in reducing disease

symptoms and laboratory parameters of inflammation [4].

Although previous reports have documented that an

association between NHL and adult rheumatic disease

treated with MTX, there is only one case of NHL in

patients with JRA treated with MTX in the literature [5,6].

We report the second case of NHL and the first case of

97 (2005) 249–252

Y. Yildirim / Gynecologic Oncology 97 (2005) 249–252250

primary ovarian NHL occurring in a JRA patient treated

with low dose MTX up today in the literature.

Case

A 17-year-old girl had previously seronegative poliartic-

ular form of JRA applied to our hospital with complaints of

chronic pelvic pain and fatigue for 7 months. She has

received low dose MTX (7.5 mg per week) for the last 3

years. She had also intermittently been treated with daily or

alternate daily prednisolone throughout the period of her

JRA. JRA was not complicated by other co-morbid medical

illness.

A physical examination revealed bilateral ovarian masses

with 8–10 cm in diameter; therefore, she was admitted for

further investigations. Full blood count, renal-hepatic

function tests, and serum electrolytes were normal. Labo-

ratory studies also showed normal levels of serum Ca-125

(13 U/ml; normal b35 U/ml), CEA (1.4 ng/ml; normal b5

ng/ml), CA 19.9 (17.6 U/ml; normal b37 U/ml), a-feto-

protein (4.8 ng/ml; normal b20 ng/ml), and lactate

dehydrogenase (LDH) (212 U/l; normal b460 U/l). In

addition to these, Epstein–Barr Virus (EBV), cytomegalo-

virus (CMV), and human immunodeficiency virus (HIV)

serologies (IgM and IgG) were negative. A thoraco–

abdominal computed tomography (CT) confirmed bilateral

ovarian tumor which had palpated in bimanual pelvic

examination. There were no signs of extra-ovarian organ

involvement and significant lymphadenopathy in locates of

abdomen, pelvis, and mediastenum.

A large abdominal vertical midline incision was

performed for the purpose of certain diagnosis. At

exploratory laparatomy, peritoneal cavity was washed with

200 ml of normal saline for cytological works, and tissue

samples from both ovarian masses were sent to frozen

section. The result of frozen section was suspicious for

malignancy. The other pelvic and upper abdominal organs

and pelvic–paraortic lymph nodes were normal macro-

scopically. There was no adherent to adjacent organs from

ovarian masses. She underwent total abdominal hyster-

ectomy with bilateral salphingo-oophorectomy (TAH–

BSO) and surgical staging including pelvic–paraortic

lymphadenectomy, appendectomy, and partial infracolic

omentectomy.

The definitive histopathologic diagnosis was made as

diffuse large cell lymphoma of the ovary after paraffin

immunostaining studies. Most of the neoplastic cells were

positive for CD20 (L-26) (B cell marker), but negative for

TdT and UCHL-1 (CD45RO) (T cell markers). Investiga-

tions made after diagnosis of malignant B lymphoma put

forth no evidence of malignant disease in central nervous

system (CNS) and bone marrow. Although both ovaries

were involved, and one of the removed pelvic lymph nodes

included tumor cells; the patient was staged as IIE according

to the Ann Arbor Staging System.

After the lymphoma, diagnosis systemic MTX treatment

was discontinued. The patient received 6 cycles of standard

CHOP regimen (Cyclophosphamide 750 mg/m2, Doxoru-

bicin 50 mg/m2, Vincristine 1.4 mg/m2, and Prednisone

50 mg/m2) later. Intrathecal MTX was given for CNS

prophylaxis.

She remained in good condition up to the 18th day after

completion of cytotoxic chemotherapy, when she developed

lymphomatous meningitis and intracranial hemorrhage. She

died 23 days after cerebral hemorrhage that led to

cardiopulmonary arrest.

Discussion

The incidence of NHL, especially extra-nodal type, has

increased in the last two decades. The cause of the increase

has not been clearly demonstrated but increasing of the HIV

infection prevalence has been accusing. On the other hand,

several risk factors have been identified that predispose

patients to the development of NHL. Patients with

congenital disorders such as Ataxia-telangiectasia, Black-

fan-Diamond Syndrome, Wiskott–Aldrich syndrome, and

Celiac disease have an increased incidence of lymphoma.

Certain acquired conditions predispose patients to NHL,

immunosuppressive therapy, Helicobacter pylori gastritis,

Hashimato’s thyroiditis, and Sjfgren syndrome. Further-

more, patients with rheumatic disease such as RA have

increased risk [7–10].

In RA patients, there are multiple factors that contribute

to increased risk such as disease activity and the type of

drug used in the treatment. However, the mechanism of

malignant lymphoma developing in these patients is clearly

unknown. The hypothesis that MTX has a role in the

etiology of NHL is supported, at least in part in adult

patients, by the observation of spontaneous remission of

lymphoma on cessation of MTX therapy [11]. Recently,

many authors have linked development of lymphoma in

patients with RA with MTX and Epstein–Barr Virus (EBV)

[6,12,13]. Although MTX usage is accused, there is no

adequate data regarding effect of MTX on carcinogenesis

and there is general acceptance that MTX is not oncogenic

[6,14]. In addition to this, the lack of reports of increased

NHL risk in other conditions treated with MTX supports

this view [15]. Because of most NHL in patients with RA

have B cell type, some authors claim that there is an

association between latent EBV infection and NHL

[6,12,13]. Patients with RA are known to have a defect in

EBV directed suppressor T cell function, which can be

increased by weekly low dose MTX administration [16,17].

However, combining two recent series of 44 NHL occurring

in MTX treated patients with RA, 13 (30%) had EBV RNA

[18,19]. Our patient had B cell NHL, and negative EBV

antibody.

Regardless of stage, 80% of primary ovarian lymphoma

presents with pelvic mass; and a small amount of cases

Y. Yildirim / Gynecologic Oncology 97 (2005) 249–252 251

present with ascites and increased serum Ca-125 level [20].

Therefore, the presentation of primary NHL may include

findings suggestive of advanced epithelial ovarian cancer.

However, frequent misdiagnoses in ovarian lymphoma

include granulose cell tumors, dysgerminoma, and meta-

static cancer [21]. Because treatment modality and prog-

nosis are very different from other neoplasms especially

granulosa cell tumors showing diffuse pattern and dysger-

minoma, diagnostic accuracy of ovarian lymphoma is

important. The presence of positive immunocytochemical

staining for leukocyte common antigen (LCA) distinguishes

malignant lymphoma from non-lymphoid neoplasms. Fur-

ther studies including B- and T-marker antibodies and

molecular studies such as gene rearrangement can be

performed in LCA-positive cases. The cytogenetic analyses

can be put forth [14,18] and somatic mutation of the

immunoglobulin gene [22]. Our patient was presented with

pelvic mass, pelvic pain, and normal serum Ca-125 level.

Certain diagnosis was made after immunocytochemical

studies. However, we were not able to do cytogenetic works.

Primary ovarian NHL as other extra-nodal non-Hodg-

kin’s lymphomas is usually classified according to the

Working Formulation (WF) and staged according to Ann

Arbor Staging System (AASS). Based upon these classi-

fication and staging system, primary ovarian lymphomas are

generally treated with debulking surgery and postoperative

chemotherapy and/or radiation therapy (RT). The most used

chemotherapy regimen is CHOP [2]. The impact of the

complete surgical staging is unclear. However, because of

the clinical manifestation of primary ovarian NHL is similar

to EOC, and therefore, it is difficult to diagnose this disease

before operation, surgical staging and debulking operation

are usually performed as in our case. Although in young

women with borderline epithelial ovarian malignancy and

adolescents with malignant germ cell ovarian tumor fertility

preserving surgery is recommended [23], there is no

consensus in this situation in which ovarian involvement

can be a part of diffuse lymphomatous process as well.

Therefore, we believe that conservative surgery must be

limited with cases of unilateral presentation. In contrary to

this, because subsequent cytotoxic chemotherapy can be

effective in the disease control [24], selective conservative

approach may be suggested in cases which were certainly

diagnosed as ovarian lymphoma by intraoperative frozen

section even if both ovaries are involved [25]. Our case,

however, had not certainly been diagnosed as lymphoma at

the time of surgical operation and we applied more a

comprehensive intervention with suspicion of epithelial

ovarian cancer.

The prognosis of ovarian lymphoma primarily depends

on clinical stage and histological type. Patients with

localized disease have a high cure rate, but advanced

disease and non-B cell type are associated with poor

prognosis [26,27]. Dimopoulos et al. reported that 57% of

all patients had 15 years survival and they also impressed

the importance of combination chemotherapy regimens

appropriate for specific histology of the lymphoma in their

retrospective study [2]. Fox et al. have reported a mean 60

months survival time for Ann Arbor Stage IIE primary

ovarian NHL [3]. However, although our case had stage IIE

disease and B cell histology, and had received prophylactic

intrathecal MTX, she died from intracranial complication

due to CNS recurrence 8th month after diagnosis.

In consequence, if stringent criteria are used for diag-

nosis, true primary ovarian lymphoma is an extremely rare

disease. Ovarian masses in JRA patients are carefully

evaluated because of increased lymphoid malignancy risk.

Although low stage and B cell type primary ovarian

lymphoma have generally good prognosis, the patients

should be carefully evaluated to survive disease recurrence

especially in CNS.

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